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Jiang M, Sun L, Jia Y, Ren X, Han L, Zhu Z, Zheng X. Causal effects of Annexin A1 and Annexin A2 on ischemic stroke and its subtypes: A two-sample Mendelian randomization study. J Cardiol 2025:S0914-5087(25)00099-1. [PMID: 40187529 DOI: 10.1016/j.jjcc.2025.03.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 03/26/2025] [Accepted: 03/27/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND Preclinical studies have suggested that Annexin A1 and Annexin A2 act as anti-inflammatory agents, slowing the progression of atherosclerosis and further potentially reducing the risk of ischemic stroke. Since the causality of Annexins and ischemic stroke remains uncertain, this study aimed to investigate the causal effects of both using a two-sample Mendelian randomization (MR) method. METHODS The genetic instruments associated with Annexin A1 and Annexin A2 originated from a European-descent genome-wide association study (GWAS) of 50,000 participants from the INTERVAL study. Summary statistics for ischemic stroke and ischemic stroke subtypes were derived from the MEGASTROKE consortium's GWAS dataset, involving 40,585 cases and 406,111 controls of European ancestry. The inverse-variance weighted method was utilized in the main analysis, followed by a series of sensitivity analyses for robustness validation. RESULTS In the primary analysis, genetically predicted high Annexin A1 levels were associated with decreased risks of ischemic stroke (OR = 0.96; 95 % CI = 0.93-0.99; p = 0.023) and large artery stroke (OR = 0.88; 95 % CI = 0.81-0.96; p = 0.004). Similarly, genetically predicted high Annexin A2 levels also had significant associations with decreased risks of ischemic stroke (OR = 0.97; 95 % CI = 0.95-1.00; p = 0.019) and large artery stroke (OR = 0.90; 95 % CI = 0.85-0.96; p = 0.001). CONCLUSION In this two-sample MR study, we found that Annexins had causal protective effects against ischemic stroke, especially large artery stroke. Further basic mechanistic studies should be conducted to investigate the biological roles of these genes.
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Affiliation(s)
- Minglan Jiang
- Public Health Research Center and Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Lulu Sun
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Yiming Jia
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Xiao Ren
- Public Health Research Center and Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Longyang Han
- Public Health Research Center and Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Zhengbao Zhu
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
| | - Xiaowei Zheng
- Public Health Research Center and Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
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Lin TY, Leu HB, Wu YW, Tseng WK, Lin TH, Yeh HI, Chang KC, Wang JH, Yin WH, Wu CC, Huang CY, Lin SJ, Hsu CY, Chen JW. Prognostic utility of neutrophil gelatinase-associated lipocalin (NGAL) levels for cardiovascular events in patients with stable coronary artery disease treated with percutaneous coronary intervention: a prospective longitudinal cohort study. Biomark Res 2025; 13:24. [PMID: 39920870 PMCID: PMC11806831 DOI: 10.1186/s40364-025-00737-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/27/2025] [Indexed: 02/09/2025] Open
Abstract
INTRODUCTION Neutrophil gelatinase-associated lipocalin (NGAL) modulates the enzymatic activity of matrix metalloproteinase-9, which is an important mediator of plaque instability in atherosclerosis. High NGAL levels can independently predict all-cause mortality and major adverse cardiac events (MACE) in patients with acute myocardial infarction (AMI). However, studies that have measured NGAL levels in patients with stable coronary artery disease (CAD) are limited. Furthermore, no significant prognostic predictive value between NGAL levels and stable CAD has been established. HYPOTHESIS We aimed to investigate the prognostic role of NGAL levels in a prospective cohort study of patients with stable CAD treated with percutaneous coronary intervention (PCI). METHODS A total of 2,238 stable patients with CAD and a previous PCI were enrolled in a multicenter prospective observational study (The National Taiwan Biosignature Research, NTBR) in Taiwan. The primary outcome was the occurrence of MACE (cardiovascular death, nonfatal myocardial infarction, and ischemic stroke). The secondary outcome was a composite of cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure). RESULTS During the mean follow-up period of 4.6 ± 1.7 years, 441 patients reached the primary endpoints. Kaplan-Meier analysis showed that event-free survival was significantly different between the first and third tertile groups (log-rank test, p < 0.001) in subjects categorized by NGAL levels. In a multivariate Cox proportional hazard regression analysis, plasma NGAL levels were independently associated with an increased risk of MACE [adjusted hazard ratio (aHR) = 1.35; 95% confidence interval (CI) = 1.18-1.54, p < 0.001], AMI (aHR = 1.34; 95% CI = 1.12-1.59, p < 0.001), and target vessel revascularization (aHR = 1.35; 95% CI = 1.19-1.53, p < 0.001). Addition of serum NGAL levels to the traditional risk model improved its prediction value for future cardiovascular events. CONCLUSIONS High plasma NGAL levels were independently associated with the occurrence of MACE and composite cardiovascular events in patients with stable PCI-treat CAD.
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Affiliation(s)
- Ting-Yu Lin
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Cardiovascular Medical Center, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Hsin-Bang Leu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Heath Care and Management Center, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yen-Wen Wu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Cardiology Division of Cardiovascular Medical Center, Department of Nuclear Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Wei-Kung Tseng
- Division of Cardiology, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
| | - Tsung-Hsien Lin
- Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hung-I Yeh
- Division of Cardiology, Department of Internal Medicine, MacKay Memorial Hospital, MacKay Medical College, New Taipei City, Taiwan
| | - Kuan-Cheng Chang
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, 404327, Taiwan
- Graduate Institute of Biomedical Sciences, Taiwan, China Medical University, Taichung, 404333, Taiwan
| | - Ji-Hung Wang
- Department of Cardiology, Buddhist Tzu-Chi General Hospital, Tzu-Chi University, Hualien, Taiwan
| | - Wei-Hsian Yin
- Heart Center, Faculty of Medicine, School of Medicine, Cheng Hsin General Hospital, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chau-Chung Wu
- Cardiology Division, Department of Internal Medicine, Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Chun-Yao Huang
- Division of Cardiology and Cardiovascular Research Center, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan
| | - Shing-Jong Lin
- Division of Cardiology and Cardiovascular Research Center, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan
| | - Chien-Yi Hsu
- Division of Cardiology and Cardiovascular Research Center, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
- Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan.
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan.
| | - Jaw-Wen Chen
- Division of Cardiology and Cardiovascular Research Center, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
- Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan.
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan.
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Zhang W, Wu Y, Yuan Y, Wang L, Yu B, Li X, Yao Z, Liang B. Identification of key biomarkers for predicting atherosclerosis progression in polycystic ovary syndrome via bioinformatics analysis and machine learning. Comput Biol Med 2024; 183:109239. [PMID: 39396400 DOI: 10.1016/j.compbiomed.2024.109239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 09/09/2024] [Accepted: 09/30/2024] [Indexed: 10/15/2024]
Abstract
OBJECTIVE Polycystic ovary syndrome (PCOS) is one of the most significant cardiovascular risk factors, playing vital roles in various cardiovascular diseases such as atherosclerosis (AS). This study attempted to explore key biomarkers for predicting AS in patients with PCOS and to investigate the role of immune cell infiltration in this process. METHODS We downloaded the expression matrix of AS (GSE100927, GSE28829) and PCOS (GSE54248) from the Gene Expression Omnibus (GEO) database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to identify PCOS-related genes in AS. Functional enrichment analysis was employed to reveal underlying mechanisms. Then, Protein-protein interaction (PPI) and three machine learning algorithms were used to screen the hub genes, including the Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and Random Forest (RF). Moreover, the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were applied to evaluate the diagnostic value of the nomogram model. Finally, we performed immune cell infiltration and single-gene GSEA. RESULTS A total of 41 genes were identified as PCOS-related genes in AS, with functional analysis indicating that the potential pathogenesis lies in inflammatory and immune responses. Furthermore, we identified two hub genes (MMP9 and P2RY13) by three machine learning algorithms. The nomogram model based on MMP9 and P2RY13 can be used as a new diagnostic model to differentiate AS in PCOS women (AUC＞0.9). The calibration curves and DCA curves demonstrated the excellent discriminative ability and clinical practicality of this nomogram. Finally, immune infiltration analysis revealed the disorder of immunocytes in AS. The two gene expressions were negatively correlated with Monocyte and Macrophages M1, while positively correlated with Macrophages M0. Single gene GSEA analysis suggested that the MMP9 and P2RY13 might be involved in the metabolism and inflammation responses. CONCLUSION We identified MMP9 and P2RY13 as the biomarkers and developed a new nomogram for early diagnosing AS based on them in PCOS patients. Our findings may provide new insights into the diagnosis, prevention, and treatment targets of PCOS-associated AS.
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Affiliation(s)
- Wenjing Zhang
- Department of Cardiology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030000, China
| | - Yalin Wu
- Department of Cardiology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030000, China
| | - Yalin Yuan
- Department of Cardiology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030000, China
| | - Leigang Wang
- Department of Cardiology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030000, China
| | - Bing Yu
- Department of Cardiology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030000, China
| | - Xin Li
- Department of Cardiology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030000, China
| | - Zhong Yao
- Department of Cardiology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030000, China
| | - Bin Liang
- Department of Cardiology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030000, China.
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Chen M, Suwannaphoom K, Sanaiha Y, Luo Y, Benharash P, Fishbein MC, Sevag Packard RR. Electrochemical impedance spectroscopy unmasks high-risk atherosclerotic features in human coronary artery disease. FASEB J 2024; 38:e70069. [PMID: 39315853 PMCID: PMC11728480 DOI: 10.1096/fj.202401200r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 08/23/2024] [Accepted: 09/10/2024] [Indexed: 09/25/2024]
Abstract
Coronary plaque rupture remains the prominent mechanism of myocardial infarction. Accurate identification of rupture-prone plaque may improve clinical management. This study assessed the discriminatory performance of electrochemical impedance spectroscopy (EIS) in human cardiac explants to detect high-risk atherosclerotic features that portend rupture risk. In this single-center, prospective study, n = 26 cardiac explants were collected for EIS interrogation of the three major coronary arteries. Vessels in which advancement of the EIS catheter without iatrogenic plaque disruption was rendered impossible were not assessed. N = 61 vessels underwent EIS measurement and histological analyses. Plaques were dichotomized according to previously established high rupture-risk parameter thresholds. Diagnostic performance was determined via receiver operating characteristic areas-under-the-curve (AUC). Necrotic cores were identified in n = 19 vessels (median area 1.53 mm2) with a median fibrous cap thickness of 62 μm. Impedance was significantly greater in plaques with necrotic core area ≥1.75 mm2 versus <1.75 mm2 (19.8 ± 4.4 kΩ vs. 7.2 ± 1.0 kΩ, p = .019), fibrous cap thickness ≤65 μm versus >65 μm (19.1 ± 3.5 kΩ vs. 6.5 ± 0.9 kΩ, p = .004), and ≥20 macrophages per 0.3 mm-diameter high-power field (HPF) versus <20 macrophages per HPF (19.8 ± 4.1 kΩ vs. 10.2 ± 0.9 kΩ, p = .002). Impedance identified necrotic core area ≥1.75 mm2, fibrous cap thickness ≤65 μm, and ≥20 macrophages per HPF with AUCs of 0.889 (95% CI: 0.716-1.000) (p = .013), 0.852 (0.646-1.000) (p = .025), and 0.835 (0.577-1.000) (p = .028), respectively. Further, phase delay discriminated severe stenosis (≥70%) with an AUC of 0.767 (0.573-0.962) (p = .035). EIS discriminates high-risk atherosclerotic features that portend plaque rupture in human coronary artery disease and may serve as a complementary modality for angiography-guided atherosclerosis evaluation.
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Affiliation(s)
- Michael Chen
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Krit Suwannaphoom
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Yas Sanaiha
- Cardiovascular Outcomes Research Laboratories, University of California, Los Angeles, CA, USA
- Division of Cardiac Surgery, Department of Surgery, David Geffen School of Medicine at University of California-Las Angeles, CA, USA
| | - Yuan Luo
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, People’s Republic of China
| | - Peyman Benharash
- Cardiovascular Outcomes Research Laboratories, University of California, Los Angeles, CA, USA
- Division of Cardiac Surgery, Department of Surgery, David Geffen School of Medicine at University of California-Las Angeles, CA, USA
| | - Michael C. Fishbein
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - René R. Sevag Packard
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA
- West Los Angeles Veterans Affairs Medical Center, Los Angeles, CA, USA
- Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA
- Molecular Biology Institute, University of California, Los Angeles, CA, USA
- California NanoSystems Institute, University of California, Los Angeles, CA, USA
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Woźniak A, Satała J, Gorzelak‐Pabiś P, Pawlos A, Broncel M, Kaźmierski P, Woźniak E. OxLDL as a prognostic biomarker of plaque instability in patients qualified for carotid endarterectomy. J Cell Mol Med 2024; 28:e18459. [PMID: 39039803 PMCID: PMC11263466 DOI: 10.1111/jcmm.18459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 04/18/2024] [Accepted: 05/16/2024] [Indexed: 07/24/2024] Open
Abstract
Atherosclerotic plaque instability increases the risk of stroke. As such, determining the nature of an instability atherosclerotic plaque may speed up qualification for carotid endarterectomy (CEA), thus reducing the risk of acute vascular events. The aim of the study was to determine the diagnostic value of oxidized LDL cholesterol (ox-LDL), matrix metalloproteinase 9 (MMP-9) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in serum as a prognostic markers of instability atherosclerotic plaques. Serum was collected from 67 patients who underwent CEA in accordance with the qualification criteria. The levels of ox-LDL, MMP-9 and 8-OHdG were assessed by ELISA. The predictive value of the markers was determined based on an ROC curve, and the cut-off points with the highest sensitivity and specificity were determined. Patients with unstable atherosclerotic plaque had significantly higher serum ox-LDL, MMP-9 and 8-OHdG values. It was found that in patients before CEA, ox-LDL >31.4 ng/mL was associated with an 82.5% probability of unstable atherosclerotic plaque, MMP-9 >113.1 ng/mL with 78.6%, and 8-OHdG >2.15 ng/mL with 64.7%. Multivariate regression analysis found ox-LDL to be an independent factor associated with plaque instability. Patients with unstable plaques tend to have higher serum levels of ox-LDL, MMP-9 and 8-OHdG compared to those with stable plaques. The optimal cut-off point for ox-LDL (AUC 0.86, p <0.0001) was 31.14 ng/mL, with 91.18% sensitivity and 78.79% specificity. The high sensitivity and specificity of ox-LDL suggests that it can be used as an independent marker of plaque instability.
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Affiliation(s)
- Agnieszka Woźniak
- Department of Internal Diseases and Clinical Pharmacology, Laboratory of Tissue ImmunopharmacologyMedical University of LodzLodzPoland
| | - Joanna Satała
- Department of Internal Diseases and Clinical Pharmacology, Laboratory of Tissue ImmunopharmacologyMedical University of LodzLodzPoland
| | - Paulina Gorzelak‐Pabiś
- Department of Internal Diseases and Clinical Pharmacology, Laboratory of Tissue ImmunopharmacologyMedical University of LodzLodzPoland
| | - Agnieszka Pawlos
- Department of Internal Diseases and Clinical Pharmacology, Laboratory of Tissue ImmunopharmacologyMedical University of LodzLodzPoland
| | - Marlena Broncel
- Department of Internal Diseases and Clinical Pharmacology, Laboratory of Tissue ImmunopharmacologyMedical University of LodzLodzPoland
| | - Piotr Kaźmierski
- Department of Vascular, General, and Oncologic SurgeryMedical University of LodzLodzPoland
| | - Ewelina Woźniak
- Department of Internal Diseases and Clinical Pharmacology, Laboratory of Tissue ImmunopharmacologyMedical University of LodzLodzPoland
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Zivkovic M, Stankovic A, Koncar I, Kolakovic A, Boskovic M, Djuric T. The MMP-9 promoter genetic variant rs3918242, mRNA and protein expression in advanced carotid plaque tissue. Mol Biol Rep 2024; 51:540. [PMID: 38642151 DOI: 10.1007/s11033-024-09458-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 03/18/2024] [Indexed: 04/22/2024]
Abstract
BACKGROUND The MMP-9 is a known player in atherosclerosis, yet associations of the MMP-9 -1562 C/T variant (rs3918242) with various atherosclerotic phenotypes and tissue mRNA expression are still contradictory. This study aimed to investigate the MMP-9 -1562 C/T variant, its mRNA and protein expression in carotid plaque (CP) tissue, as a risk factor for CP presence and as a marker of different plaque phenotypes (hyperechoic and hypoechoic) in patients undergoing carotid endarterectomy. The MnSOD as an MMP-9 negative regulator was also studied in relation to CP phenotypes. METHODS AND RESULTS Genotyping of 770 participants (285 controls/485 patients) was done by tetra-primer ARMS PCR. The MMP-9 mRNA expression in 88 human CP tissues was detected by TaqMan® technology. The protein levels of MMP-9 and MnSOD were assessed by Western blot analysis. The MMP-9 -1562 C/T variant was not recognized as a risk factor for plaque presence or in predisposing MMP-9 mRNA and protein levels in plaque tissue. Patients with hypoechoic plaques had significantly lower MMP-9 mRNA and protein levels than those with hyperechoic plaque (p = 0.008, p = 0.003, respectively). MnSOD protein level was significantly higher in hypoechoic plaque compared to hyperechoic (p = 0.039). MMP-9 protein expression in CP tissue was significantly affected by sex and plaque type interaction (p = 0.009). CONCLUSIONS Considering the differences of MMP-9 mRNA and protein expression in CP tissue regarding different plaque phenotypes and the observed sex-specific effect, the role of MMP-9 in human atherosclerotic plaques should be further elucidated.
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Grants
- 451-03-66/2024-03/200017 The Ministry of Science, Technological Development and Innovation, Republic of Serbia
- 451-03-66/2024-03/200017 The Ministry of Science, Technological Development and Innovation, Republic of Serbia
- 451-03-66/2024-03/200017 The Ministry of Science, Technological Development and Innovation, Republic of Serbia
- 451-03-66/2024-03/200017 The Ministry of Science, Technological Development and Innovation, Republic of Serbia
- 451-03-66/2024-03/200017 The Ministry of Science, Technological Development and Innovation, Republic of Serbia
- 451-03-66/2024-03/200017 The Ministry of Science, Technological Development and Innovation, Republic of Serbia
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Affiliation(s)
- Maja Zivkovic
- Laboratory for Radiobiology and Molecular Genetics, VINCA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovica Alasa 12-14, P.O. Box 522, Vinca, Belgrade, 11351, Serbia.
| | - Aleksandra Stankovic
- Laboratory for Radiobiology and Molecular Genetics, VINCA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovica Alasa 12-14, P.O. Box 522, Vinca, Belgrade, 11351, Serbia
| | - Igor Koncar
- Clinic for Vascular and Endovascular Surgery, Clinical Center of Serbia, Dr Koste Todorovica 8, Belgrade, 11000, Serbia
- Medical Faculty, University of Belgrade, Dr Subotica 8, Belgrade, 11000, Serbia
| | - Ana Kolakovic
- Laboratory for Radiobiology and Molecular Genetics, VINCA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovica Alasa 12-14, P.O. Box 522, Vinca, Belgrade, 11351, Serbia
| | - Maja Boskovic
- Laboratory for Radiobiology and Molecular Genetics, VINCA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovica Alasa 12-14, P.O. Box 522, Vinca, Belgrade, 11351, Serbia
| | - Tamara Djuric
- Laboratory for Radiobiology and Molecular Genetics, VINCA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovica Alasa 12-14, P.O. Box 522, Vinca, Belgrade, 11351, Serbia
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Miceli G, Basso MG, Pintus C, Pennacchio AR, Cocciola E, Cuffaro M, Profita M, Rizzo G, Tuttolomondo A. Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review. Int J Mol Sci 2024; 25:4351. [PMID: 38673936 PMCID: PMC11050267 DOI: 10.3390/ijms25084351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 04/05/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
The concept of vulnerable carotid plaques is pivotal in understanding the pathophysiology of ischemic stroke secondary to large-artery atherosclerosis. In macroscopic evaluation, vulnerable plaques are characterized by one or more of the following features: microcalcification; neovascularization; lipid-rich necrotic cores (LRNCs); intraplaque hemorrhage (IPH); thin fibrous caps; plaque surface ulceration; huge dimensions, suggesting stenosis; and plaque rupture. Recognizing these macroscopic characteristics is crucial for estimating the risk of cerebrovascular events, also in the case of non-significant (less than 50%) stenosis. Inflammatory biomarkers, such as cytokines and adhesion molecules, lipid-related markers like oxidized low-density lipoprotein (LDL), and proteolytic enzymes capable of degrading extracellular matrix components are among the key molecules that are scrutinized for their associative roles in plaque instability. Through their quantification and evaluation, these biomarkers reveal intricate molecular cross-talk governing plaque inflammation, rupture potential, and thrombogenicity. The current evidence demonstrates that plaque vulnerability phenotypes are multiple and heterogeneous and are associated with many highly complex molecular pathways that determine the activation of an immune-mediated cascade that culminates in thromboinflammation. This narrative review provides a comprehensive analysis of the current knowledge on molecular biomarkers expressed by symptomatic carotid plaques. It explores the association of these biomarkers with the structural and compositional attributes that characterize vulnerable plaques.
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Affiliation(s)
- Giuseppe Miceli
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Maria Grazia Basso
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Chiara Pintus
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Andrea Roberta Pennacchio
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Elena Cocciola
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Mariagiovanna Cuffaro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Martina Profita
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Giuliana Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Antonino Tuttolomondo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
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8
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Fan CH, Tsai CY, Lai CY, Liou YF, Lee JK, Yeh CK. Feasibility of in vitro calcification plaque disruption using ultrasound-induced microbubble inertial cavitation. ULTRASONICS 2024; 138:107238. [PMID: 38183758 DOI: 10.1016/j.ultras.2023.107238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 12/28/2023] [Accepted: 12/28/2023] [Indexed: 01/08/2024]
Abstract
Percutaneous transluminal coronary angioplasty (PTCA) is a clinical method in which plaque-narrowed arteries are widened by inflating an intravascular balloon catheter. However, PTCA remains challenging to apply in calcified plaques since the high pressure required for achieving a therapeutic outcome can result in balloon rupture, vessel rupture, and intimal dissection. To address the problem with PTCA, we hypothesized that a calcified plaque can be disrupted by microbubbles (MBs) inertial cavitation induced by ultrasound (US). This study proposed a columnar US transducer with a novel design to generate inertial cavitation at the lesion site. Experiments were carried out using tubular calcification phantom to mimic calcified plaques. After different parameters of US + MBs treatment (four types of MBs concentration, five types of cycle number, and three types of insonication duration; n = 4 in each group), inflation experiments were performed to examine the efficacy of cavitation for a clinically used balloon catheter. Finally, micro-CT was used to investigate changes in the internal structure of the tubular plaster phantoms. The inflation threshold of the untreated tubular plaster phantoms was > 11 atm, and this was significantly reduced to 7.4 ± 0.7 atm (p = 5.2E-08) using US-induced MBs inertial cavitation at a treatment duration of 20 min with an acoustic pressure of 214 kPa, an MBs concentration of 4.0 × 108 MBs/mL, a cycle number of 100 cycles, and a pulse repetition frequency of 100 Hz. Moreover, micro-CT revealed internal damage in the tubular calcification phantom, demonstrating that US-induced MBs inertial cavitation can effectively disrupt calcified plaques and reduce the inflation threshold of PTCA. The ex vivo histopathology results showed that the endothelium of pig blood vessels remained intact after the treatment. In summary, the results show that US-induced MBs inertial cavitation can markedly reduce the inflation threshold in PTCA without damaging blood vessel endothelia, indicating the potential of the proposed treatment method.
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Affiliation(s)
- Ching-Hsiang Fan
- Department of Biomedical Engineering, National Cheng Kung University, Tainan 701, Taiwan; Medical Device Innovation Center, National Cheng Kung University, Tainan 701, Taiwan
| | - Chieh-Yu Tsai
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Chun-Yen Lai
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Ya-Fu Liou
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Jen-Kuang Lee
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10617, Taiwan
| | - Chih-Kuang Yeh
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan.
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9
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Alvarez MM, Salazar FE, Rodriguez T, D’Egidio F, Borlongan CV, Lee JY. Endogenous Extracellular Vesicles Participate in Brain Remodeling after Ischemic Stroke. Int J Mol Sci 2023; 24:16857. [PMID: 38069179 PMCID: PMC10706116 DOI: 10.3390/ijms242316857] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/21/2023] [Accepted: 11/26/2023] [Indexed: 12/18/2023] Open
Abstract
Brain remodeling after an ischemic stroke represents a promising avenue for exploring the cellular mechanisms of endogenous brain repair. A deeper understanding of these mechanisms is crucial for optimizing the safety and efficacy of neuroprotective treatments for stroke patients. Here, we interrogated the role of extracellular vesicles, particularly exosomes, as potential mediators of endogenous repair within the neurovascular unit (NVU). We hypothesized that these extracellular vesicles may play a role in achieving transient stroke neuroprotection. Using the established ischemic stroke model of middle cerebral artery occlusion in adult rats, we detected a surged in the extracellular vesicle marker CD63 in the peri-infarct area that either juxtaposed or co-localized with GFAP-positive glial cells, MAP2-labeled young neurons, and VEGF-marked angiogenic cells. This novel observation that CD63 exosomes spatially and temporally approximated glial activation, neurogenesis, and angiogenesis suggests that extracellular vesicles, especially exosomes, contribute to the endogenous repair of the NVU, warranting exploration of extracellular vesicle-based stroke therapeutics.
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Affiliation(s)
| | | | | | | | - Cesar V. Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA; (M.M.A.); (F.E.S.); (T.R.); (F.D.); (J.-Y.L.)
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10
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Alsharif B, Hante N, Govoni B, Verli H, Kukula-Koch W, Jose Santos-Martinez M, Boylan F. Capparis cartilaginea decne (capparaceae): isolation of flavonoids by high-speed countercurrent chromatography and their anti-inflammatory evaluation. Front Pharmacol 2023; 14:1285243. [PMID: 37927588 PMCID: PMC10620733 DOI: 10.3389/fphar.2023.1285243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/10/2023] [Indexed: 11/07/2023] Open
Abstract
Introduction: Capparis cartilaginea Decne. (CC) originates from the dry regions of Asia and the Mediterranean basin. In traditional medicine, tea of CC leaves is commonly used to treat inflammatory conditions such as rheumatism, arthritis, and gout. Due to the limited studies on the phytochemistry and biological activity of CC compared to other members of the Capparaceae family, this work aims to: 1) Identify the chemical composition of CC extract and 2) Investigate the potential anti-inflammatory effect of CC extract, tea and the isolated compounds. Methods: To guarantee aim 1, high-speed countercurrent chromatography (HSCC) method; Nuclear Magnetic Resonance (NMR) and High-Performance Liquid Chromatography coupled to Electrospray Ionisation and Quadrupole Time-of-Flight Mass Spectrometry (HPLC-ESIQTOF-MS/MS) were employed for this purpose. To guarantee aim 2, we studied the effect of the isolated flavonoids on matrix metalloproteinases (MMPs) -9 and -2 in murine macrophages. Molecular docking was initially performed to assess the binding affinity of the isolated flavonoids to the active site of MMP-9. Results and discussion: In silico model was a powerful tool to predict the compounds that could strongly bind and inhibit MMPs. CC extract and tea have shown to possess a significant antioxidant and anti-inflammatory effect, which can partially explain their traditional medicinal use.
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Affiliation(s)
- Bashaer Alsharif
- School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Department of Pharmacognosy, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Nadhim Hante
- School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Faculty of Pharmacy, University of Kufa, Al-Najaf, Iraq
| | - Bruna Govoni
- Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Hugo Verli
- Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Wirginia Kukula-Koch
- Department of Pharmacognosy with Medicinal Plants Garden, Medical University of Lublin, Lublin, Poland
| | - María Jose Santos-Martinez
- School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Fabio Boylan
- School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
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11
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Slysz J, Sinha A, DeBerge M, Singh S, Avgousti H, Lee I, Glinton K, Nagasaka R, Dalal P, Alexandria S, Wai CM, Tellez R, Vescovo M, Sunderraj A, Wang X, Schipma M, Sisk R, Gulati R, Vallejo J, Saigusa R, Lloyd-Jones DM, Lomasney J, Weinberg S, Ho K, Ley K, Giannarelli C, Thorp EB, Feinstein MJ. Single-cell profiling reveals inflammatory polarization of human carotid versus femoral plaque leukocytes. JCI Insight 2023; 8:e171359. [PMID: 37471165 PMCID: PMC10544225 DOI: 10.1172/jci.insight.171359] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 07/17/2023] [Indexed: 07/22/2023] Open
Abstract
Femoral atherosclerotic plaques are less inflammatory than carotid plaques histologically, but limited cell-level data exist regarding comparative immune landscapes and polarization at these sites. We investigated intraplaque leukocyte phenotypes and transcriptional polarization in 49 patients undergoing femoral (n = 23) or carotid (n = 26) endarterectomy using single-cell RNA-Seq (scRNA-Seq; n = 13), flow cytometry (n = 24), and IHC (n = 12). Comparative scRNA-Seq of CD45+-selected leukocytes from femoral (n = 9; 35,265 cells) and carotid (n = 4; 30,655 cells) plaque revealed distinct transcriptional profiles. Inflammatory foam cell-like macrophages and monocytes comprised higher proportions of myeloid cells in carotid plaques, whereas noninflammatory foam cell-like macrophages and LYVE1-overexpressing macrophages comprised higher proportions of myeloid cells in femoral plaque (P < 0.001 for all). A significant comparative excess of CCR2+ macrophages in carotid versus plaque was observed by flow cytometry in a separate validation cohort. B cells were more prevalent and exhibited a comparatively antiinflammatory profile in femoral plaque, whereas cytotoxic CD8+ T cells were more prevalent in carotid plaque. In conclusion, human femoral plaques exhibit distinct macrophage phenotypic and transcriptional profiles as well as diminished CD8+ T cell populations compared with human carotid plaques.
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Affiliation(s)
| | - Arjun Sinha
- Division of Cardiology, Department of Medicine
| | | | | | | | - Inhyeok Lee
- Division of Cardiology, Department of Medicine
| | - Kristofor Glinton
- Division of Cardiology, Department of Medicine
- Department of Pathology, and
| | | | | | - Shaina Alexandria
- Department of Preventive Medicine at Northwestern University Feinberg School of Medicine (NUFSM), Chicago, Illinois, USA
| | - Ching Man Wai
- Northwestern University Sequencing Core, Chicago, Illinois, USA
| | - Ricardo Tellez
- Division of Cardiology, Department of Medicine
- Department of Pathology, and
| | | | | | - Xinkun Wang
- Northwestern University Sequencing Core, Chicago, Illinois, USA
| | - Matthew Schipma
- Northwestern University Sequencing Core, Chicago, Illinois, USA
| | - Ryan Sisk
- Division of Cardiology, Department of Medicine
| | - Rishab Gulati
- La Jolla Institute of Immunology, La Jolla, California, USA
| | | | | | - Donald M. Lloyd-Jones
- Division of Cardiology, Department of Medicine
- Department of Preventive Medicine at Northwestern University Feinberg School of Medicine (NUFSM), Chicago, Illinois, USA
| | | | | | - Karen Ho
- Division of Vascular Surgery, NUFSM, Chicago, Illinois, USA
| | - Klaus Ley
- Immunology Center of Georgia, Augusta, Georgia, USA
| | - Chiara Giannarelli
- Department of Medicine and
- Department of Pathology, New York University, New York, New York, USA
| | | | - Matthew J. Feinstein
- Division of Cardiology, Department of Medicine
- Department of Pathology, and
- Department of Preventive Medicine at Northwestern University Feinberg School of Medicine (NUFSM), Chicago, Illinois, USA
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12
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Bräuninger H, Krüger S, Bacmeister L, Nyström A, Eyerich K, Westermann D, Lindner D. Matrix metalloproteinases in coronary artery disease and myocardial infarction. Basic Res Cardiol 2023; 118:18. [PMID: 37160529 PMCID: PMC10169894 DOI: 10.1007/s00395-023-00987-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/11/2023]
Abstract
Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. Most cardiovascular deaths are caused by ischaemic heart diseases such as myocardial infarction (MI). Hereby atherosclerosis in the coronary arteries often precedes disease manifestation. Since tissue remodelling plays an important role in the development and progression of atherosclerosis as well as in outcome after MI, regulation of matrix metalloproteinases (MMPs) as the major ECM-degrading enzymes with diverse other functions is crucial. Here, we provide an overview of the expression profiles of MMPs in coronary artery and left ventricular tissue using publicly available data from whole tissue to single-cell resolution. To approach an association between MMP expression and the development and outcome of CVDs, we further review studies investigating polymorphisms in MMP genes since polymorphisms are known to have an impact on gene expression. This review therefore aims to shed light on the role of MMPs in atherosclerosis and MI by summarizing current knowledge from publically available datasets, human studies, and analyses of polymorphisms up to preclinical and clinical trials of pharmacological MMP inhibition.
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Affiliation(s)
- Hanna Bräuninger
- Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Side Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Saskia Krüger
- Clinic for Cardiology, University Heart and Vascular Centre Hamburg, Hamburg, Germany
| | - Lucas Bacmeister
- Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany
| | - Alexander Nyström
- Department of Dermatology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Kilian Eyerich
- Department of Dermatology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dirk Westermann
- Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany
| | - Diana Lindner
- Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
- German Centre for Cardiovascular Research (DZHK), Partner Side Hamburg/Kiel/Lübeck, Hamburg, Germany.
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13
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Macchi C, Sirtori CR, Corsini A, Mannuccio Mannucci P, Ruscica M. Pollution from fine particulate matter and atherosclerosis: A narrative review. ENVIRONMENT INTERNATIONAL 2023; 175:107923. [PMID: 37119653 DOI: 10.1016/j.envint.2023.107923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/27/2023] [Accepted: 04/05/2023] [Indexed: 05/22/2023]
Abstract
According to the WHO, the entire global population is exposed to air pollution levels higher than recommended for health preservation. Air pollution is a complex mixture of nano- to micro-sized particles and gaseous components that poses a major global threat to public health. Among the most important air pollutants, causal associations have been established between particulate matter (PM), mainly < 2.5 μm, and cardiovascular diseases (CVD), i.e., hypertension, coronary artery disease, ischemic stroke, congestive heart failure, arrhythmias as well as total cardiovascular mortality. Aim of this narrative review is to describe and critically discuss the proatherogenic effects of PM2.5 that have been attributed to many direct or indirect effects comprising endothelial dysfunction, a chronic low-grade inflammatory state, increased production of reactive oxygen species, mitochondrial dysfunction and activation of metalloproteases, all leading to unstable arterial plaques. Higher concentrations of air pollutants are associated with the presence of vulnerable plaques and plaque ruptures witnessing coronary artery instability. Air pollution is often disregarded as a CVD risk factor, in spite of the fact that it is one of the main modifiable factors relevant for prevention and management of CVD. Thus, not only structural actions should be taken in order to mitigate emissions, but health professionals should also take care to counsel patients on the risks of air pollution.
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Affiliation(s)
- Chiara Macchi
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy
| | - Cesare R Sirtori
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy
| | - Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy
| | - Pier Mannuccio Mannucci
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
| | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy; Department of Cardio-Thoracic-Vascular Diseases - Foundation IRCCS Cà Granda Ospedale Maggiore Policlinico, Italy.
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14
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Liu YL, Chiang JT, Ko PF. The benefits of tourism for rural community development. HUMANITIES & SOCIAL SCIENCES COMMUNICATIONS 2023; 10:137. [PMID: 37016690 PMCID: PMC10064601 DOI: 10.1057/s41599-023-01610-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 03/06/2023] [Indexed: 06/19/2023]
Abstract
While the main benefits of rural tourism have been studied extensively, most of these studies have focused on the development of sustainable rural tourism. The role of tourism contributions to rural community development remains unexplored. Little is known about what tourism contribution dimensions are available for policy-makers and how these dimensions affect rural tourism contributions. Without a clear picture and indication of what benefits rural tourism can provide for rural communities, policy-makers might not invest limited resources in such projects. The objectives of this study are threefold. First, we outline a rural tourism contribution model that policy-makers can use to support tourism-based rural community development. Second, we address several methodological limitations that undermine current sustainability model development and recommend feasible methodological solutions. Third, we propose a six-step theoretical procedure as a guideline for constructing a valid contribution model. We find four primary attributes of rural tourism contributions to rural community development; economic, sociocultural, environmental, and leisure and educational, and 32 subattributes. Ultimately, we confirm that economic benefits are the most significant contribution. Our findings have several practical and methodological implications and could be used as policy-making guidelines for rural community development.
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Affiliation(s)
- Yung-Lun Liu
- Chienkuo Technology University, Changhua, Taiwan
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15
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Aggarwal A, Jennings CL, Manning E, Cameron SJ. Platelets at the Vessel Wall in Non-Thrombotic Disease. Circ Res 2023; 132:775-790. [PMID: 36927182 PMCID: PMC10027394 DOI: 10.1161/circresaha.122.321566] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 02/15/2023] [Indexed: 03/18/2023]
Abstract
Platelets are small, anucleate entities that bud from megakaryocytes in the bone marrow. Among circulating cells, platelets are the most abundant cell, traditionally involved in regulating the balance between thrombosis (the terminal event of platelet activation) and hemostasis (a protective response to tissue injury). Although platelets lack the precise cellular control offered by nucleate cells, they are in fact very dynamic cells, enriched in preformed RNA that allows them the capability of de novo protein synthesis which alters the platelet phenotype and responses in physiological and pathological events. Antiplatelet medications have significantly reduced the morbidity and mortality for patients afflicted with thrombotic diseases, including stroke and myocardial infarction. However, it has become apparent in the last few years that platelets play a critical role beyond thrombosis and hemostasis. For example, platelet-derived proteins by constitutive and regulated exocytosis can be found in the plasma and may educate distant tissue including blood vessels. First, platelets are enriched in inflammatory and anti-inflammatory molecules that may regulate vascular remodeling. Second, platelet-derived microparticles released into the circulation can be acquired by vascular endothelial cells through the process of endocytosis. Third, platelets are highly enriched in mitochondria that may contribute to the local reactive oxygen species pool and remodel phospholipids in the plasma membrane of blood vessels. Lastly, platelets are enriched in proteins and phosphoproteins which can be secreted independent of stimulation by surface receptor agonists in conditions of disturbed blood flow. This so-called biomechanical platelet activation occurs in regions of pathologically narrowed (atherosclerotic) or dilated (aneurysmal) vessels. Emerging evidence suggests platelets may regulate the process of angiogenesis and blood flow to tumors as well as education of distant organs for the purposes of allograft health following transplantation. This review will illustrate the potential of platelets to remodel blood vessels in various diseases with a focus on the aforementioned mechanisms.
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Affiliation(s)
- Anu Aggarwal
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, Ohio
| | - Courtney L. Jennings
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, Ohio
| | - Emily Manning
- Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Scott J. Cameron
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, Ohio
- Heart Vascular and Thoracic Institute, Department of Cardiovascular Medicine, Section of Vascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA
- Case Western Reserve University School of Medicine, Cleveland, Ohio
- Department of Hematology, Taussig Cancer Center, Cleveland, Ohio
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16
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Metformin Directly Binds to MMP-9 to Improve Plaque Stability. J Cardiovasc Dev Dis 2023; 10:jcdd10020054. [PMID: 36826550 PMCID: PMC9962015 DOI: 10.3390/jcdd10020054] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/19/2023] [Accepted: 01/27/2023] [Indexed: 02/01/2023] Open
Abstract
Vulnerable atherosclerotic plaque rupture is the principal mechanism that accounts for myocardial infarction and stroke. High matrix metalloproteinase-9 (MMP-9) expression and activity have been proven to lead to plaque instability. Metformin, a first-line treatment for type 2 diabetes, is beneficial to plaque vulnerability. However, the mechanism underlying its anti-atherogenic effect remains unclear. Molecular docking and surface plasmon resonance experiments showed that metformin directly interacts with MMP-9, and incubated MMP-9 overexpressing HEK293A cells with metformin (1 μmol·L-1) significantly attenuates MMP-9's activity using zymography and MMP activity assays. Moreover, metformin treatment drives MMP-9 degradation. Next, we constructed a carotid artery atherosclerotic plaque model and administered consecutive 14-day metformin (200 mg·kg-1·d-1) treatment by intragastric gavage. Immunofluorescence staining of the right carotid common artery and serum MMP activity assay results showed that metformin treatment decreased local plaque MMP-9 protein level and circulating MMP-9 activity, respectively. Histochemical staining revealed that after metformin treatment, the collagen content in plaque was significantly preserved, and the plaque vulnerability index decreased. These findings suggested that metformin improved atherosclerotic plaque stability by directly binding to MMP-9 and driving its degradation.
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17
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Sef D, Kovacevic M, Jernej B, Novacic K, Slavica M, Petrak J, Medved I, Milosevic M. Immunohistochemical analysis of MMP-9 and COX-2 expression in carotid atherosclerotic plaques among patients undergoing carotid endarterectomy: A prospective study. J Stroke Cerebrovasc Dis 2022; 31:106731. [PMID: 36075131 DOI: 10.1016/j.jstrokecerebrovasdis.2022.106731] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/27/2022] [Accepted: 08/14/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Matrix metalloproteinase-9 protein (MMP-9) and cyclooxygenase-2 (COX-2) proteins may have a role in remodelling of atherosclerotic plaques. We analysed and compared the radiological, histological and immunohistochemical characteristics of carotid atherosclerotic plaques between symptomatic and asymptomatic patients who underwent carotid endarterectomy (CEA). METHODS This prospective single-blinded study included 31 patients (70 [64-75] years, 58% males, 42% symptomatic) who underwent CEA and a total of 155 carotid plaque sections that were analysed. Preoperative assessment and multimodality diagnostic imaging with magnetic resonance imaging (MRI) or computed tomography angiography (CTA), histological and immunohistochemical analyses of carotid plaques including the expression of MMP-9 and COX-2 proteins were performed. RESULTS Symptomatic and asymptomatic patients did not significantly differ in respect to preoperative characteristics. Unstable plaques were detected in 12/13 (92.3%, p = 0.020) symptomatic patients using MRI or CTA. There was no perioperative mortality and perioperative outcomes were comparable in both groups. A significantly higher expression of MMP-9 in macrophages was observed among symptomatic patients (p = 0.020). ROC curve analysis showed statistically significant associations of both the higher intensity of COX-2 staining in CD68 PG-M1 positive macrophages (area under the curve [AUC]=0.701, p = 0.014) and higher MVD (AUC=0.821, p < 0.001) within the plaque with cerebrovascular symptoms. The expression of COX-2 and the intensity of COX-2 staining in macrophages within the unstable carotid plaques detected by preoperative MRI or CTA were significantly higher (76.1% vs. 40.0%, p = 0.038; 76.2% vs. 30.0%, p = 0.01, respectively). CONCLUSIONS Advanced non-invasive multimodality diagnostic imaging including MRI or CTA is reliable in differentiating unstable from stable carotid plaques. High expression of MMP-9 and COX-2 in macrophages within the symptomatic plaque is associated with increased risk of cerebrovascular complications. TRIAL REGISTRATION This study has been registered at the ISRCTN registry (ID ISRCTN46536832), isrctn.org Identifier: https://www.isrctn.com/ISRCTN46536832.
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Affiliation(s)
- Davorin Sef
- Department of Cardiac Surgery, Harefield Hospital, Royal Brompton and Harefield Hospitals, Part of Guy's and St. Thomas' NHS Foundation Trust, London, UK.
| | - Miljenko Kovacevic
- Department of Vascular Surgery, University Hospital Centre Rijeka, Rijeka, Croatia, EU
| | - Bojan Jernej
- Polyclinic for Radiology and Neurology "Dijagnostika 2000", Zagreb, Croatia, EU
| | - Karlo Novacic
- Department of Diagnostic and Interventional Radiology, University Hospital Centre Zagreb, Zagreb, Croatia, EU
| | - Marko Slavica
- Department of Diagnostic and Interventional Radiology, University Hospital Merkur, Zagreb, Croatia, EU
| | - Jelka Petrak
- University of Zagreb, School of Medicine, Zagreb, Croatia, EU
| | - Igor Medved
- Department of Cardiac Surgery, University Hospital Centre Rijeka, Rijeka, Croatia, EU
| | - Milan Milosevic
- University of Zagreb, School of Medicine, Zagreb, Croatia, EU; Andrija Stampar School of Public Health, Zagreb, Croatia, EU
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18
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Gkaliagkousi E, Lazaridis A, Dogan S, Fraenkel E, Tuna BG, Mozos I, Vukicevic M, Yalcin O, Gopcevic K. Theories and Molecular Basis of Vascular Aging: A Review of the Literature from VascAgeNet Group on Pathophysiological Mechanisms of Vascular Aging. Int J Mol Sci 2022; 23:ijms23158672. [PMID: 35955804 PMCID: PMC9368987 DOI: 10.3390/ijms23158672] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 07/25/2022] [Accepted: 07/29/2022] [Indexed: 11/29/2022] Open
Abstract
Vascular aging, characterized by structural and functional alterations of the vascular wall, is a hallmark of aging and is tightly related to the development of cardiovascular mortality and age-associated vascular pathologies. Over the last years, extensive and ongoing research has highlighted several sophisticated molecular mechanisms that are involved in the pathophysiology of vascular aging. A more thorough understanding of these mechanisms could help to provide a new insight into the complex biology of this non-reversible vascular process and direct future interventions to improve longevity. In this review, we discuss the role of the most important molecular pathways involved in vascular ageing including oxidative stress, vascular inflammation, extracellular matrix metalloproteinases activity, epigenetic regulation, telomere shortening, senescence and autophagy.
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Affiliation(s)
- Eugenia Gkaliagkousi
- 3rd Department of Internal Medicine, Papageorgiou Hospital, Faculty of Medicine, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece
- Correspondence: (E.G.); (K.G.)
| | - Antonios Lazaridis
- 3rd Department of Internal Medicine, Papageorgiou Hospital, Faculty of Medicine, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece
| | - Soner Dogan
- Department of Medical Biology, School of Medicine, Yeditepe University, 34755 Istanbul, Turkey
| | - Emil Fraenkel
- 1st Department of Internal Medicine, University Hospital, Pavol Jozef Šafárik University of Košice, Trieda SNP 1, 04066 Košice, Slovakia
| | - Bilge Guvenc Tuna
- Department of Biophysics, School of Medicine, Yeditepe University, 34755 Istanbul, Turkey
| | - Ioana Mozos
- Department of Functional Sciences-Pathophysiology, Center for Translational Research and Systems Medicine, “Victor Babes” University of Medicine and Pharmacy, 300173 Timisoara, Romania
| | - Milica Vukicevic
- Cardiac Surgery Clinic, Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Ozlem Yalcin
- Department of Physiology, School of Medicine, Koc University, 34450 Istanbul, Turkey
| | - Kristina Gopcevic
- Laboratory for Analytics of Biomolecules, Department of Chemistry in Medicine, Faculty of Medicine, 11000 Belgrade, Serbia
- Correspondence: (E.G.); (K.G.)
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19
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Impact of MMP-9 Genetic Polymorphism and Concentration on the Development of Coronary Artery Disease in Ukrainian Population. Cardiol Res Pract 2022; 2022:2067632. [PMID: 35449607 PMCID: PMC9017573 DOI: 10.1155/2022/2067632] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 02/18/2022] [Accepted: 03/22/2022] [Indexed: 02/01/2023] Open
Abstract
Coronary artery disease (CAD) is one of the leading causes of death in Europe. It is known that atherosclerosis is the primary risk factor of CAD development. MMP-9 is involved in all stages of atherosclerosis and thus may contribute to CAD emergence. To investigate the influence of MMP-9 on the (CAD) development 25 patients with intact coronary arteries (CA), 40 patients with acute coronary syndrome (ACS), and 63 patients with chronic coronary syndrome (CCS) were enrolled in the study. Real-time PCR was carried out for genotyping on the rs17567-polymorphic locus, and ELISA study was performed to measure the MMP-9 plasma concentration. It was found the lower risk of MI occurrence for AG-carriers (
; ORa = 0.299, 95% CI = 0.106–0.848) in Ukrainian population.
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20
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Sef D, Milosevic M, Ostric M, Mestrovic T, Jernej B, Kovacic S, Kovacevic M, Skrtic A, Vidjak V. The role of magnetic resonance imaging and the expression of MMP-9 protein in the analysis of carotid atherosclerotic plaques in patients undergoing carotid endarterectomy: a prospective pilot study. Rev Cardiovasc Med 2021; 22:1611-1620. [PMID: 34957802 DOI: 10.31083/j.rcm2204167] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/22/2021] [Accepted: 09/27/2021] [Indexed: 09/01/2023] Open
Abstract
Components of carotid atherosclerotic plaque can be analysed preoperatively by non-invasive advanced imaging modalities such as magnetic resonance imaging (MRI). The expression of matrix metalloproteinase-9 protein (MMP-9), which has a potential role in remodelling of atherosclerotic plaques, can be analysed immunohistochemically. The aim of the present prospective pilot study is to analyse histological characteristics and expression of MMP-9 in carotid plaques of patients undergoing carotid endarterectomy (CEA) and to investigate the correlation with preoperative clinical symptoms and MRI features. Preoperative clinical assessment, MRI imaging, postoperative histological and immunohistochemical analyses were performed. Fifteen patients with symptomatic (7/15; 47%) and asymptomatic carotid artery stenosis undergoing CEA were included. Among symptomatic patients, 5 (71%) had recent stroke and 2 (29%) had recent transient ischaemic attack with a median timing of 6 weeks (IQR: 1, 18) before the surgery. Both groups did not significantly differ in respect to preoperative characteristics. Prevalence of unstable plaque was higher in symptomatic than asymptomatic patients, although it was not significant (63% vs. 37%, p = 0.077). The expression of MMP-9 in CD68 cells within the plaque by semiquantitative analysis was found to be significantly higher in symptomatic as compared to asymptomatic patients (86% vs. 25% with the highest expression, p = 0.014). The average microvascular density was found to be higher and lipid core area larger among both symptomatic patients and unstable carotid plaque specimens, although this did not reach statistical significance (p = 0.064 and p = 0.132, p = 0.360 and p = 0.569, respectively). Our results demonstrate that MRI is reliable in classifying carotid lesions and differentiating unstable from stable plaques. We have also shown that the expression of MMP-9 is significantly higher among symptomatic patients undergoing CEA.
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Affiliation(s)
- Davorin Sef
- Department of Cardiac Surgery, The Barts Heart Centre, St. Bartholomew's Hospital, Barts Health NHS Trust, EC1A 7BE London, UK
| | - Milan Milosevic
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Andrija Stampar School of Public Health, 10000 Zagreb, Croatia
| | - Marin Ostric
- Department of Cardiac Surgery, University Hospital Centre Rijeka, 51000 Rijeka, Croatia
| | - Tomislav Mestrovic
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Department of Vascular Surgery, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
| | - Bojan Jernej
- Polyclinic for Radiology and Neurology "Dijagnostika 2000", 10000 Zagreb, Croatia
| | - Slavica Kovacic
- Department of Radiology, University Hospital Centre Rijeka, 51000 Rijeka, Croatia
- School of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Miljenko Kovacevic
- School of Medicine, University of Rijeka, 51000 Rijeka, Croatia
- Department of Vascular Surgery, University Hospital Centre Rijeka, 51000 Rijeka, Croatia
| | - Anita Skrtic
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Department of Pathology, University Hospital Merkur, 10000 Zagreb, Croatia
| | - Vinko Vidjak
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Department of Diagnostic and Interventional Radiology, University Hospital Merkur, 10000 Zagreb, Croatia
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21
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Huang S, Wu X, Zhang L, Wu J, He Y, Lai M, Xu J, Li Z. Assessment of Carotid Plaque Stability Using Contrast-Enhanced Ultrasound and Its Correlation With the Expression of CD147 and MMP-9 in the Plaque. Front Comput Neurosci 2021; 15:778946. [PMID: 34924986 PMCID: PMC8672308 DOI: 10.3389/fncom.2021.778946] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 10/18/2021] [Indexed: 11/13/2022] Open
Abstract
This study aims to investigate the correlation between the enhancement degree of contrast-enhanced ultrasound (CEUS) and the expression of CD147 and MMP-9 in carotid atherosclerotic plaques in patients with carotid endarterectomy and evaluate the diagnostic efficacy of CEUS using pathological results as the gold standard. Thirty-eight patients who underwent carotid endarterectomy (CEA) for carotid stenosis in the Department of Neurovascular Surgery of the Second People’s Hospital of Shenzhen from July 2019 to June 2020 were selected. Preoperatively, two-dimensional (2D) ultrasound scan was performed on all patients to assess the characteristics of the plaque and degree of stenosis, and CEUS was used to evaluate the surface morphology of the plaque and the distribution of neovascularization. Postoperatively, pathological sections and immunohistochemical analysis of CD147 and MMP-9 levels in the plaque were performed on the stripped plaque tissue, and the results were analyzed against the CEUS grading and pathological results. Among the 38 patients, pathological results showed that 10 and 28 were in the stable and vulnerable plaque groups, respectively. There were more smokers in the vulnerable plaque group than in the stable plaque group, with higher intraplaques CD147 and MMP-9. The difference in ultrasound plaque surface morphology grading and CEUS grading between the two groups was statistically significant. There was no significant difference in age, sex, incidence of complications such as hypertension, diabetes, and coronary heart disease between the two groups. CD147 was higher in the CEUS grade IV group than in the grades I (P = 0.040) and II (P = 0.010) groups. MMP-9 was higher in the CEUS grade IV group than in the grade II group (P = 0.017); MMP-9 was higher in the grade III group than in the grade II group (P = 0.015). Intraplaque contrast enhancement intensity was positively correlated with CD147 (r = 0.462, P = 0.003) and MMP-9 (r = 0.382, P = 0.018) levels. There was moderate consistency between the assessment of plaque vulnerability by 2D-ultrasound and by histopathological hematoxylin-eosin (HE) (kappa = 0.457, P > 0.05). 2D diagnosis of vulnerable plaque had a sensitivity of 85.7%, a specificity of 60.0%, a positive predictive value of 85.7%, a negative predictive value of 60.0%, and an accuracy of 78.0%. There was a strong consistency between the assessment of plaque vulnerability by CEUS and histopathological HE (kappa = 0.671, P < 0.01). CEUS had a sensitivity of 89.2%, a specificity of 80.0%, a positive predictive value of 92.6%, a negative predictive value of 72.7%, and an accuracy of 86.8% for the diagnosis of vulnerable plaques; CEUS is a reliable, non-invasive test that can show the distribution of neovascularization within vulnerable plaques, evaluate the vulnerability and risk of intraplaque hemorrhage, with a high consistency with pathological findings. The degree of intraplaque enhancement and the levels of CD147 and MMP-9 in the tissue were positively correlated.
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Affiliation(s)
- Shanshan Huang
- Department of Ultrasound, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Xinyin Wu
- Department of Ultrasound, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Linlin Zhang
- Department of Ultrasound, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Jianming Wu
- Department of Neurosurgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Yi He
- Department of Neurosurgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Manlin Lai
- Department of Ultrasound, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Jiaqi Xu
- Department of Ultrasound, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Zhenzhou Li
- Department of Ultrasound, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
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22
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Conforti A, Wahlers T, Paunel-Görgülü A. Neutrophil extracellular traps modulate inflammatory markers and uptake of oxidized LDL by human and murine macrophages. PLoS One 2021; 16:e0259894. [PMID: 34797846 PMCID: PMC8604363 DOI: 10.1371/journal.pone.0259894] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/29/2021] [Indexed: 01/23/2023] Open
Abstract
Neutrophil extracellular traps (NETs) are web-like structures, which are released upon neutrophil activation. It has previously been demonstrated that NETs are present in atherosclerotic lesions of both humans and animal models thus playing a decisive role in atherosclerosis. Besides, macrophages have a crucial role in disease progression, whereby classically activated M1 macrophages sustain inflammation and alternatively activated M2 macrophages display anti-inflammatory effects. Although NETs and macrophages were found to colocalize in atherosclerotic lesions, the impact of NETs on macrophage function is not fully understood. In the present study, we aimed to investigate the effect of NETs on human and murine macrophages in respect to the expression of pro-inflammatory cytokines, matrix metalloproteinases (MMPs) and uptake of oxidized LDL (oxLDL) in vitro. Human THP-1 and murine bone marrow-derived macrophages were cultured under M1 (LPS + IFN-γ)- and M2a (IL-4)-polarizing culture conditions and treated with NETs. To mimic intraplaque regions, cells were additionally cultured under hypoxic conditions. NETs significantly increased the expression of IL-1β, TNF-α and IL-6 in THP-M1 macrophages under normoxia but suppressed their expression in murine M1 macrophages under hypoxic conditions. Notably, NETs increased the number of oxLDL-positive M1 and M2 human and murine macrophages under normoxia, but did not influence formation of murine foam cells under hypoxia. However, oxLDL uptake did not strongly correlate with the expression of the LDL receptor CD36. Besides, upregulated MMP-9 expression and secretion by macrophages was detected in the presence of NETs. Again, hypoxic culture conditions dampened NETs effects. These results suggest that NETs may favor foam cell formation and plaque vulnerability, but exert opposite effects in respect to the inflammatory response of human and murine M1 macrophages. Moreover, effects of NETs on macrophages’ phenotype are altered under hypoxia.
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Affiliation(s)
- Andreas Conforti
- Department of Cardiothoracic Surgery, Heart Center of The University of Cologne, Cologne, Germany
| | - Thorsten Wahlers
- Department of Cardiothoracic Surgery, Heart Center of The University of Cologne, Cologne, Germany
| | - Adnana Paunel-Görgülü
- Department of Cardiothoracic Surgery, Heart Center of The University of Cologne, Cologne, Germany
- * E-mail:
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23
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Jaeger M, Stratmann B, Tschoepe D. Peripheral oscillometric arterial performance does not depict coronary status in patients with type 2 diabetes mellitus. Diab Vasc Dis Res 2021; 18:14791641211046522. [PMID: 34825586 PMCID: PMC8743959 DOI: 10.1177/14791641211046522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Arterial stiffness is associated with cardiovascular events. Matrix metalloproteases (MMPs), their tissue inhibitors (TIMPs) and galectin-3 are involved in the pathogenesis of end organ damage. This study aimed to evaluate the contribution of arterial stiffness, MMPs, TIMPs and galectin-3 with the current vascular status in type 2 diabetes mellitus (T2DM). METHODS 74 patients with T2DM, 36 with coronary heart disease (CHD) (T2DM + CHD) and 38 without CHD (T2DM - CHD) were included. Aortic pulse wave velocity (PWVao), aortic and brachial augmentation indices (AIx aortic and AIx brachial) and central-aortic blood pressure values were determined by non-invasive arteriography. MMPs, TIMPs and galectin-3 plasma concentrations were analysed by ELISA. RESULTS Patients with T2DM and CHD presented with significantly increased arterial stiffness determined as AIx and significantly elevated values for TIMP-4 and galectin-3. Heterogeneous peripheral vascular status regardless of the CHD status was observed, and increasing severity of CHD was associated with an increased arterial stiffness. TIMP-4 correlated significantly with an elevated PWVao in the whole cohort independently from CHD status. CONCLUSION Determination of arterial stiffness is an effective and, compared to laboratory markers, more reliable method for determining the peripheral vascular situation in patients with T2DM, but it does not clearly depict coronary situation.
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Affiliation(s)
- Magdalene Jaeger
- Herz- und Diabeteszentrum NRW, 39059Ruhr Universität Bochum, Bad Oeynhausen, Germany
| | - Bernd Stratmann
- Herz- und Diabeteszentrum NRW, 39059Ruhr Universität Bochum, Bad Oeynhausen, Germany
| | - Diethelm Tschoepe
- Herz- und Diabeteszentrum NRW, 39059Ruhr Universität Bochum, Bad Oeynhausen, Germany
- Stiftung DHD (Der herzkranke Diabetiker) Stiftung in der Deutschen Diabetes-Stiftung, Bad Oeynhausen, Germany
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24
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Chen DY, Su PJ, See LC, Liu JR, Chuang CK, Pang ST, Tseng CN, Chen SW, Hsieh IC, Chu PH, Lin YC, Hsu CL, Chang JWC, Lin MS, Pang JHS, Hsieh MJ, Huang WK. Gonadotropin-releasing hormone antagonist associated with lower cardiovascular risk compared with gonadotropin-releasing hormone agonist in prostate cancer: A nationwide cohort and in vitro study. Prostate 2021; 81:902-912. [PMID: 34196430 DOI: 10.1002/pros.24187] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 05/29/2021] [Accepted: 06/07/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND We aimed to determine whether cardiovascular (CV) risk in patients with prostate cancer (PCa) differs between those who receive gonadotropin-releasing hormone (GnRH) agonist (GnRHa) therapy and those who receive GnRH antagonist therapy. METHODS Using the Taiwan National Health Insurance Research Database, we analyzed data by comparing 666 participants receiving GnRH antagonists and 1332 propensity score-matched participants treated with GnRHa in a 1:2 fashion during the period from May 1, 2015, to September 30, 2018. Cox proportional-hazards models were used to estimate the treatment effect on CV outcomes. Furthermore, we conducted an in vitro study to investigate the effect of a GnRHa (leuprolide) or a GnRH antagonist (degarelix) on matrix metalloproteinase-9 (MMP-9) expression and invasion ability in THP-1 differentiated macrophages. RESULTS GnRH antagonist therapy was associated with a lower risk of composite CV events of myocardial infarction, ischemic stroke, or CV death (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.25-0.90) than GnRHa therapy, with a mean follow-up period of 1.21 years. Significantly lower risks of CV death (HR, 0.21; 95% CI, 0.06-0.70) and all-cause mortality (HR, 0.77; 95% CI, 0.61-0.97) were observed in the GnRH antagonist group. In the in vitro study, leuprolide, but not degarelix, significantly increased the expression of MMP-9 activity and the invasive ability of THP-1 differentiated macrophages through gelatin zymography and the matrix invasion assay, respectively. CONCLUSION GnRH antagonists were associated with reduced risk CV events compared with the GnRHa among patients with PCa, which may be through effects on macrophages.
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Affiliation(s)
- Dong-Yi Chen
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Po-Jung Su
- Division of Hematology/Oncology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Lai-Chu See
- Department of Public Health, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Biostatistics Core Laboratory, Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Jia-Rou Liu
- Department of Public Health, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Keng Chuang
- Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - See-Tong Pang
- Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chi-Nan Tseng
- Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Shao-Wei Chen
- Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - I-Chang Hsieh
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Pao-Hsien Chu
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Yung-Chang Lin
- Division of Hematology/Oncology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Cheng-Lung Hsu
- Division of Hematology/Oncology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - John Wen-Cheng Chang
- Division of Hematology/Oncology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Miao-Sui Lin
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Jong-Hwei S Pang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital Linkou, Taiwan
| | - Ming-Jer Hsieh
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Wen-Kuan Huang
- Division of Hematology/Oncology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
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25
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Zhao J, Yang M, Wu J. CXCL16 may be a predisposing factor to atherosclerosis: An animal study. Mol Med Rep 2021; 24:716. [PMID: 34396447 DOI: 10.3892/mmr.2021.12355] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 12/29/2020] [Indexed: 11/06/2022] Open
Abstract
Atherosclerosis (AS) is a chronic inflammatory process initiated when lipoprotein is retained in the arterial wall. Leukocyte recruitment accelerates this process. CXC chemokine ligand 16 (CXCL16) acts as a chemokine to attract immune cells and also facilitates the phagocytosis process of modified low‑density lipoprotein. Whether CXCL16 promotes or inhibits the pathological process of AS remains to be elucidated. To clarify this, CXCL16 gene was introduced into C57BL/6J wild‑type mice to establish a stable CXCL16 overexpression mouse model. The initial changes of AS in mice were induced by high‑fat diet (HFD). To study how the interaction of HFD and CXCL16 affected fatty acid metabolism and deposition, body weight and plasma lipid profile were assessed. Soluble CXCL16, matrix metalloproteinase‑9, monocyte chemoattractant protein‑1 and intercellular adhesion molecule‑1 were detected by immunohistochemistry and ELISA to identify how CXCL16 affects AS lesion formation. The present study suggested that overexpression of CXCL16 combined with HFD lead to atherogenesis by upregulating the aforementioned inflammatory related genes at a protein level. The present study was the first, to the best of the authors' knowledge, to build a CXCL16 homozygous transgenic mice model to study how overexpressed CXCL16 is associated with AS for intervening in the occurrence and development of AS.
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Affiliation(s)
- Junbi Zhao
- Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Menglin Yang
- Department of Burns, Plastic Surgery and Dermatology, No. 922 Hospital of Joint Support Unit of the People's Liberation Army Hengyang, Hunan 421002, P.R. China
| | - Jie Wu
- Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
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26
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Alhazmi H, Bani-Sadr A, Bochaton T, Paccalet A, Da Silva CC, Buisson M, Amaz C, Ameli R, Berthezene Y, Eker OF, Ovize M, Cho TH, Nighoghossian N, Mechtouff L. Large vessel cardioembolic stroke and embolic stroke of undetermined source share a common profile of matrix metalloproteinase-9 level and susceptibility vessel sign length. Eur J Neurol 2021; 28:1977-1983. [PMID: 33682255 DOI: 10.1111/ene.14806] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 02/28/2021] [Accepted: 03/02/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Embolic stroke of undetermined source (ESUS) accounts for up to 25% of ischemic strokes. Identification of biomarkers that could improve the prediction of stroke subtype and subsequently of stroke prevention still remains a major issue. METHODS The HIBISCUS-STROKE cohort includes ischemic stroke patients with large vessel occlusion treated with mechanical thrombectomy following admission magnetic resonance imaging. Presence and length of susceptibility vessel sign (SVS) were assessed by gradient-recalled echo T2*-weighted imaging. Matrix metalloproteinase-9 (MMP-9) was measured on sera collected at admission. A multiple logistic regression model was performed to detect independent markers distinguishing cardioembolic (CE) from large-artery atherosclerosis (LAA) subtype. RESULTS A total of 147 patients were included, of them the etiology was distributed as follows: 86 (58.5%) CE, 26 (17.7%) LAA, and 35 (23.8%) ESUS. The optimal cutoff for differentiating CE from LAA subtype was 14.5 mm for SVS length (sensitivity, 79.7%; specificity, 72.7%) and 1110 ng/ml for admission MMP-9 level (sensitivity, 85.3%; specificity, 52.2%). Multivariate analysis revealed that current smoking (odds ratio [OR] 0.07, 95% confidence interval [CI] 0.01-0.93), tandem occlusion (OR 0.01, 95% CI 0.01-0.21), SVS length (OR 0.78, 95% CI 0.63-0.97), and admission MMP-9 level (OR 0.99, 95% CI 0.99-1.00) were inversely associated with CE subtype. SVS length and MMP-9 level did not differ between ESUS and CE subtypes. CONCLUSION SVS length and admission MMP-9 level may improve the prediction of CE subtype whose profile is close to ESUS, thus suggesting a common cardiac embolic source.
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Affiliation(s)
- Hanan Alhazmi
- Stroke Center, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
| | - Alexandre Bani-Sadr
- Neuroradiology Department, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
| | - Thomas Bochaton
- Cardiac Intensive Care Unit, Louis Pradel Hospital, Hospices Civils de Lyon, Bron, France.,CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
| | - Alexandre Paccalet
- CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
| | - Claire Crola Da Silva
- CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
| | - Marielle Buisson
- Clinical Investigation Center, INSERM 1407, Louis Pradel Hospital, Hospices Civils de Lyon, Bron, France
| | - Camille Amaz
- Clinical Investigation Center, INSERM 1407, Louis Pradel Hospital, Hospices Civils de Lyon, Bron, France
| | - Roxana Ameli
- Neuroradiology Department, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
| | - Yves Berthezene
- Neuroradiology Department, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France.,CREATIS, CNRS UMR 5220, INSERM U1044, University Lyon 1, Lyon, France
| | - Omer Faruk Eker
- Neuroradiology Department, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France.,CREATIS, CNRS UMR 5220, INSERM U1044, University Lyon 1, Lyon, France
| | - Michel Ovize
- CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France.,Clinical Investigation Center, INSERM 1407, Louis Pradel Hospital, Hospices Civils de Lyon, Bron, France
| | - Tae-Hee Cho
- Stroke Center, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France.,CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
| | - Norbert Nighoghossian
- Stroke Center, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France.,CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
| | - Laura Mechtouff
- Stroke Center, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France.,CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
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Liu YG, Yan JL, Ji YQ, Nie WJ, Jiang Y. Black mulberry ethanol extract attenuates atherosclerosis-related inflammatory factors and downregulates PPARγ and CD36 genes in experimental atherosclerotic rats. Food Funct 2021; 11:2997-3005. [PMID: 32236255 DOI: 10.1039/c9fo02736j] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Atherosclerosis (AS) is the pathological basis of various vascular diseases and currently is seriously affecting human health. Numerous studies have paid more attention to natural medicines with anti-AS properties. As a traditional Uygur folk medicine, black mulberry fruits are conventionally used in the prevention and treatment of cardiovascular diseases in southern Xinjiang of China, and their underlying mechanisms remain unknown. Our previous study revealed that the ethanol extract of black mulberry (EEBM) inhibited AS development by improving lipid metabolism abnormalities, enhancing anti-oxidative activities, and reducing atherosclerotic lesions of atherosclerotic rats. Based on this, our objective was to further investigate the effects of EEBM on the expression of AS-related inflammatory factors and the key genes PPARγ and CD36 of the ox-LDL-PPARγ-CD36 feed-forward cycle in experimental atherosclerotic rats. Black mulberry fruits were extracted with acid ethanol and chromatographed on an AB-8 macroporous resin to obtain EEBM. All experimental rats were randomly divided into five groups: normal, model, model plus simvastatin (5 mg/kg d·body weight), and model plus low-dose and high-dose EEBM groups (105 and 210 mg/kg d·body weight, respectively). Serum levels of the inflammatory factors were determined by enzyme-linked immunosorbent assay (ELISA). The mRNA and protein expression of PPARγ and CD36 in atherosclerotic rats' liver tissue and thoracic aorta were determined by Q-PCR and western blot analysis, respectively. EEBM at high dose effectively attenuated the abnormally expressed AS-related inflammatory factors of TNF-α, IL-6, MMP-9, and CRP in atherosclerotic rats by 41.5%, 66.1%, 77.5%, and 79.5%, respectively. After treatment with high dose EEBM, the elevated-expressions of PPARγ and CD36 at the mRNA and protein levels in atherosclerotic rats were found to be obviously downregulated at both levels. These results demonstrate that EEBM might lessen the AS-related inflammatory reaction, and then inhibit the formation of ox-LDL, consequently downregulating the expression of PPARγ and CD36 at the mRNA and protein levels, thus reducing macrophage-foam-cell formation and prohibiting the development of atherosclerotic plaque through the ox-LDL-PPARγ-CD36 feed-forward cycle, which can effectively prevent the occurrence and development of AS in atherosclerotic rats.
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Affiliation(s)
- Yun-Guo Liu
- College of Life Sciences, Linyi University, Linyi 276005, China
| | - Jia-Li Yan
- Department of Laboratory Medicine, Chengdu Medical College, Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-origin Food, Chengdu, 610500, China.
| | - Yan-Qing Ji
- College of Life Sciences, Linyi University, Linyi 276005, China
| | - Wen-Jing Nie
- Changji Vocational and Technical College, Changji, 831100, Xinjiang, China
| | - Yan Jiang
- Department of Laboratory Medicine, Chengdu Medical College, Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-origin Food, Chengdu, 610500, China.
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Close Association of Matrix Metalloproteinase-9 Levels With the Presence of Thin-Cap Fibroatheroma in Acute Coronary Syndrome Patients: Assessment by Optical Coherence Tomography and Intravascular Ultrasonography. CARDIOVASCULAR REVASCULARIZATION MEDICINE 2021; 32:5-10. [PMID: 33485858 DOI: 10.1016/j.carrev.2020.12.033] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/25/2020] [Accepted: 12/28/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND Thin-cap fibroatheroma (TCFA) has been suggested as a precursor lesion of coronary plaque rupture. As elevated plasma matrix metalloproteinase-9 (MMP-9) levels have been documented in patients with acute coronary syndrome (ACS), we sought to determine whether the presence of TCFA is linked to MMP-9 levels in these patients. METHODS We evaluated 51 ACS patients with de novo culprit lesions who were examined via optical coherence tomography and intravascular ultrasound. Blood samples were obtained from the peripheral vein (PV) and the ostium and culprit lesion of the infarct-related coronary artery (CA) in the acute phase of ACS and from the PV in the chronic phase (8 months after ACS). RESULTS The plasma MMP-9 level in the acute phase was significantly higher than that in the chronic phase. Plasma MMP-9 levels at the culprit lesion of the infarct-related CA were significantly higher than, but positively correlated with those in the PV (10.9 (5.9-16.1) ng/mL and 8.9 (5.6-13.0) ng/mL, p < 0.0001, respectively; Spearman ρ = 0.84, p < 0.0001). Significantly higher PV plasma MMP-9 levels were observed in patients with TCFA than in patients without TCFA (12.1 (7.0-13.5) and 5.7 (4.0-8.2) ng/ml, p<0.0001, respectively). Further, plasma MMP-9 levels in the PV were positively correlated with the remodeling index (Spearman ρ = 0.29, p = 0.039) and negatively correlated with fibrous cap thickness (Spearman ρ = -0.42, p = 0.0021). Receiver operating characteristic curve analysis showed that the plasma MMP-9 levels in the PV could predict the presence of TCFA at a cut-off value of 9.9 ng/mL. CONCLUSIONS Plasma MMP-9 levels were closely associated with MMP-9 levels in the CA and were further linked with TCFA in patients with ACS.
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Silva H, Francisco R, Saraiva A, Francisco S, Carrascosa C, Raposo A. The Cardiovascular Therapeutic Potential of Propolis-A Comprehensive Review. BIOLOGY 2021; 10:biology10010027. [PMID: 33406745 PMCID: PMC7823408 DOI: 10.3390/biology10010027] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 12/22/2020] [Accepted: 12/29/2020] [Indexed: 02/07/2023]
Abstract
Simple Summary Propolis, also described as bee glue, is a natural component made up of a resinous mixture of honeybee compounds from multiple botanical sources. The literature has demonstrated a variety of medicinal properties attributed to propolis due to its chemical complexity. However, the positive effects of propolis on cardiovascular health have gained little coverage. Therefore, we aimed to provide an accurate and up-to-date review of the main cardiovascular health benefits of propolis. In particular, we intend to establish the key varieties of propolis and pharmacological compounds with the therapeutic effects that are most encouraging, as well as the physiological processes by which those advantages are accomplished. The Brazilian green and red varieties reveal the greatest number of beneficial activities among the varieties of propolis studied. While much of the cardiovascular beneficial effects appear to derive from the cumulative actions of several compounds working via multiple signaling mechanisms, some individual compounds that may enhance the existing therapeutic arsenal have also shown significant results. It is also worth exploring the prospect of using propolis as food supplements. Abstract Owing to its chemical richness, propolis has a myriad of therapeutic properties. To the authors’ knowledge, this is the first comprehensive review paper on propolis to focus exclusively on its major effects for cardiovascular health. The propolis compound varieties with the most promising therapeutic benefits and their respective physiological mechanisms will be discussed. Propolis displays an anti-atherosclerotic activity, attained through modulation of the plasma lipid profile and through stabilization of the fatty plaque by inhibiting macrophage apoptosis, vascular smooth muscle proliferation and metalloproteinase activity. The antihypertensive effects of propolis probably arise through the combination of several mechanisms, including the suppression of catecholamine synthesis, stimulation of endothelium-dependent vasorelaxation and vascular anti-inflammatory activity. The anti-hemostatic activity of propolis is attributed to the inhibition of platelet plug formation and antifibrinolytic activity. By inhibiting the secretion of proangiogenic factors, propolis suppresses endothelial cell migration and tubulogenesis, exerting antiangiogenic activity. The antioxidant and anti-inflammatory activities are responsible for protection against vascular endothelial and cardiomyocyte dysfunction, mostly by the prevention of oxidative stress. Among the reviewed propolis varieties, the Brazilian green and red varieties show the largest number of beneficial activities. Further research, especially preclinical, should be conducted to assess the cardiovascular benefits of the given varieties with different compositions.
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Affiliation(s)
- Henrique Silva
- Informetrics Research Group, Ton Duc Thang University, Ho Chi Minh City 758307, Vietnam
- Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City 758307, Vietnam
- Correspondence: (H.S.); (A.R.)
| | - Rafaela Francisco
- Pharmacological Sciences Department, Faculty of Pharmacy, Universidade de Lisboa, Av Prof Gama Pinto, 1649-003 Lisboa, Portugal;
| | - Ariana Saraiva
- Department of Animal Pathology and Production, Bromatology and Food Technology, Faculty of Veterinary, Universidad de Las Palmas de Gran Canaria, Trasmontaña s/n, 35413 Arucas, Spain; (A.S.); (C.C.)
| | - Simone Francisco
- Faculty of Medicine, Nutrition Lab—Universidade de Lisboa, 1649-028 Lisboa, Portugal;
| | - Conrado Carrascosa
- Department of Animal Pathology and Production, Bromatology and Food Technology, Faculty of Veterinary, Universidad de Las Palmas de Gran Canaria, Trasmontaña s/n, 35413 Arucas, Spain; (A.S.); (C.C.)
| | - António Raposo
- CBIOS (Research Center for Biosciences and Health Technologies), Universidade Lusófona de Humanidades e Tecnologias, Campo Grande 376, 1749-024 Lisboa, Portugal
- Correspondence: (H.S.); (A.R.)
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Sofogianni A, Tziomalos K, Koletsa T, Pitoulias AG, Skoura L, Pitoulias GA. Using Serum Biomarkers for Identifying Unstable Carotid Plaque: Update of Current Evidence. Curr Pharm Des 2021; 27:1899-1903. [PMID: 33183188 DOI: 10.2174/1381612826666201112094734] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 08/11/2020] [Indexed: 11/22/2022]
Abstract
Carotid atherosclerosis is responsible for a great proportion of ischemic strokes. Early identification of unstable or vulnerable carotid plaques, and therefore, of patients at high risk for stroke, is of significant medical and socioeconomical value. We reviewed the current literature and discussed the potential role of the most important serum biomarkers in identifying patients with carotid atherosclerosis who are at high risk for atheroembolic stroke.
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Affiliation(s)
- Areti Sofogianni
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
| | - Konstantinos Tziomalos
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
| | - Triantafyllia Koletsa
- Department of Pathology, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
| | - Apostolos G Pitoulias
- Division of Vascular Surgery, Second Department of Surgery, Medical School, Aristotle University of Thessaloniki, G. Gennimatas Hospital, Thessaloniki, Greece
| | - Lemonia Skoura
- Department of Microbiology, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
| | - Georgios A Pitoulias
- Division of Vascular Surgery, Second Department of Surgery, Medical School, Aristotle University of Thessaloniki, G. Gennimatas Hospital, Thessaloniki, Greece
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Kook H, Jang DH, Kim JH, Cho JY, Joo HJ, Cho SA, Park JH, Hong SJ, Yu CW, Lim DS. Identification of plaque ruptures using a novel discriminative model comprising biomarkers in patients with acute coronary syndrome. Sci Rep 2020; 10:20228. [PMID: 33214686 PMCID: PMC7677551 DOI: 10.1038/s41598-020-77413-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 10/26/2020] [Indexed: 12/11/2022] Open
Abstract
Soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1), neutrophil gelatinase-associated lipocalin (NGAL), and matrix metalloproteinase-9 (MMP-9) are inflammatory biomarkers involved in plaque destabilization resulting in acute coronary syndrome (ACS). This study aimed to investigate the diagnostic value of a combination of biomarkers to discriminate plaque ruptures in the setting of ACS. Eighty-five ACS patients with optical coherence tomography (OCT) images of the culprit plaque were included and categorized into two groups: ACS with plaque rupture (Rupture group, n = 42) or without plaque rupture (Non-rupture group, n = 43) verified by OCT. A discriminative model of plaque rupture using several biomarkers was developed and validated. The Rupture group had higher white blood cell (WBC) counts and peak creatine kinase-myocardial band (CK-MB) levels (13.39 vs. 2.69 ng/mL, p = 0.0016). sLOX-1 (227.9 vs. 51.7 pg/mL, p < 0.0001) and MMP-9 (13.4 vs. 6.45 ng/mL, p = 0.0313) levels were significantly higher in the Rupture group, whereas NGAL showed a trend without statistical significance (59.03 vs. 53.80 ng/mL, p = 0.093). Receiver operating characteristic curves to differentiate Rupture group from Non-rupture group calculated the area under the curve for sLOX-1 (p < 0.001), MMP-9 (p = 0.0274), and NGAL (p = 0.0874) as 0.763, 0.645, and 0.609, respectively. A new combinatorial discriminative model including sLOX-1, MMP-9, WBC count, and the peak CK-MB level showed an area under the curve of 0.8431 (p < 0.001). With a cut-off point of 0.614, the sensitivity and specificity of plaque rupture were 62.2% and 97.6%, respectively. The new discriminative model using sLOX-1, MMP-9, WBC count, and peak CK-MB levels could better identify plaque rupture than each individual biomarker in ACS patients.
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Affiliation(s)
- Hyungdon Kook
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University School of Medicine, #73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Korea
| | - Duck Hyun Jang
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University School of Medicine, #73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Korea
| | - Jong-Ho Kim
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University School of Medicine, #73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Korea
| | - Jae-Young Cho
- Department of Cardiovascular Medicine, Regional Cardiocerebrovascular Center, Wonkwang University Medical Center, Iksan, Korea
| | - Hyung Joon Joo
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University School of Medicine, #73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Korea
| | - Sang-A Cho
- Health Insurance Review and Assessment Service, Wonju, Korea
| | - Jae Hyoung Park
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University School of Medicine, #73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Korea
| | - Soon Jun Hong
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University School of Medicine, #73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Korea
| | - Cheol Woong Yu
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University School of Medicine, #73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Korea.
| | - Do-Sun Lim
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University School of Medicine, #73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Korea.
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The Role of Matrix Metalloproteinase-9 in Atherosclerotic Plaque Instability. Mediators Inflamm 2020; 2020:3872367. [PMID: 33082709 PMCID: PMC7557896 DOI: 10.1155/2020/3872367] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 08/10/2020] [Accepted: 09/23/2020] [Indexed: 02/07/2023] Open
Abstract
Matrix metalloproteinase-9 (MMP-9) belongs to the MMP family and has been widely investigated. Excessive MMP-9 expression can enhance extracellular matrix degradation and promote plaque instability. Studies have demonstrated that MMP-9 levels are higher in vulnerable plaques than in stable plaques. Additionally, several human studies have demonstrated that MMP-9 may be a predictor of atherosclerotic plaque instability and a risk factor for future adverse cardiovascular and cerebrovascular events. MMP-9 deficiency or blocking MMP-9 expression can inhibit plaque inflammation and prevent atherosclerotic plaque instability. All of these results suggest that MMP-9 may be a useful predictive biomarker for vulnerable atherosclerotic plaques, as well as a therapeutic target for preventing atherosclerotic plaque instability. In this review, we describe the structure, function, and regulation of MMP-9. We also discuss the role of MMP-9 in predicting and preventing atherosclerotic plaque instability.
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The Prognostic Utility of Plasma NGAL Levels in ST Segment Elevation in Myocardial Infarction Patients. Adv Prev Med 2020; 2020:4637043. [PMID: 32908709 PMCID: PMC7477595 DOI: 10.1155/2020/4637043] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/20/2020] [Accepted: 08/24/2020] [Indexed: 01/06/2023] Open
Abstract
Introduction Plasma neutrophil gelatinase-associated lipocalin (NGAL) levels in acute myocardial infarction (AMI) patients are markedly higher. In addition, plasma NGAL levels were increased in patients with acute and chronic heart failure as a complication of myocardial infarction. In this study, we investigated whether there is a difference between the prognostic use of plasma NGAL levels in ST-elevation myocardial infarction (STEMI) patients with preserved and reduced left ventricular ejection fraction (LVEF). Methods 235 consecutive STEMI patients were enrolled in the study. Patients were divided into groups according to LVEF. Plasma NGAL, troponin I, creatine kinase MB (CKMB), and C-reactive protein (CRP) were measured. Finally, the study population examined with 34 reduced LVEF and 34 preserved LVEF consisted of a total of 68 patients (12 females; mean age, 61.5 ± 14.7). All patients were followed up prospectively for 6 months. This study group was divided into two subgroups as the patients who died (n = 14) and survived (n = 34), and plasma NGAL levels of the groups were compared. Results The median of NGAL was 190.08 ng/ml. Age, troponin I, CKMB, CRP, glomerular filtration rate, and creatinine were higher in reduced LVEF groups. Plasma NGAL levels were also higher in reduced LVEF than in preserved LVEF, but statistically not significant (p=0.07). Plasma NGAL levels were significantly higher in death patients than in survived patients (p < 0.001). In ROC curve analysis, the level to detect isolated cardiovascular mortality with a sensitivity of 86% and a specificity of 77% was 190 ng/mL for NGAL. Conclusion Plasma NGAL levels can be used to predict cardiovascular mortality in STEMI patients.
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34
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Extracellular vesicle signalling in atherosclerosis. Cell Signal 2020; 75:109751. [PMID: 32860954 PMCID: PMC7534042 DOI: 10.1016/j.cellsig.2020.109751] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/20/2020] [Accepted: 08/21/2020] [Indexed: 12/12/2022]
Abstract
Atherosclerosis is a major cardiovascular disease and in 2016, the World Health Organisation (WHO) estimated 17.5 million global deaths, corresponding to 31% of all global deaths, were driven by inflammation and deposition of lipids into the arterial wall. This leads to the development of plaques which narrow the vessel lumen, particularly in the coronary and carotid arteries. Atherosclerotic plaques can become unstable and rupture, leading to myocardial infarction or stroke. Extracellular vesicles (EVs) are a heterogeneous population of vesicles secreted from cells with a wide range of biological functions. EVs participate in cell-cell communication and signalling via transport of cargo including enzymes, DNA, RNA and microRNA in both physiological and patholophysiological settings. EVs are present in atherosclerotic plaques and have been implicated in cellular signalling processes in atherosclerosis development, including immune responses, inflammation, cell proliferation and migration, cell death and vascular remodeling during progression of the disease. In this review, we summarise the current knowledge regarding EV signalling in atherosclerosis progression and the potential of utilising EV signatures as biomarkers of disease.
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Matrix Metalloproteinases as Biomarkers of Atherosclerotic Plaque Instability. Int J Mol Sci 2020; 21:ijms21113946. [PMID: 32486345 PMCID: PMC7313469 DOI: 10.3390/ijms21113946] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/27/2020] [Accepted: 05/29/2020] [Indexed: 02/07/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases responsible for tissue remodeling and degradation of extracellular matrix (ECM) proteins. MMPs may modulate various cellular and signaling pathways in atherosclerosis responsible for progression and rupture of atherosclerotic plaques. The effect of MMPs polymorphisms and the expression of MMPs in both the atherosclerotic plaque and plasma was shown. They are independent predictors of atherosclerotic plaque instability in stable coronary heart disease (CHD) patients. Increased levels of MMPs in patients with advanced cardiovascular disease (CAD) and acute coronary syndrome (ACS) was associated with future risk of cardiovascular events. These data confirm that MMPs may be biomarkers in plaque instability as they target in potential drug therapies for atherosclerosis. They provide important prognostic information, independent of traditional risk factors, and may turn out to be useful in improving risk stratification.
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Chen Y, Waqar AB, Nishijima K, Ning B, Kitajima S, Matsuhisa F, Chen L, Liu E, Koike T, Yu Y, Zhang J, Chen YE, Sun H, Liang J, Fan J. Macrophage-derived MMP-9 enhances the progression of atherosclerotic lesions and vascular calcification in transgenic rabbits. J Cell Mol Med 2020; 24:4261-4274. [PMID: 32126159 PMCID: PMC7171347 DOI: 10.1111/jcmm.15087] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 11/01/2019] [Accepted: 01/10/2020] [Indexed: 12/11/2022] Open
Abstract
Matrix metalloproteinase‐9 (MMP‐9), or gelatinase B, has been hypothesized to be involved in the progression of atherosclerosis. In the arterial wall, accumulated macrophages secrete considerable amounts of MMP‐9 but its pathophysiological functions in atherosclerosis have not been fully elucidated. To examine the hypothesis that macrophage‐derived MMP‐9 may affect atherosclerosis, we created MMP‐9 transgenic (Tg) rabbits to overexpress the rabbit MMP‐9 gene under the control of the scavenger receptor A enhancer/promoter and examined their susceptibility to cholesterol diet‐induced atherosclerosis. Tg rabbits along with non‐Tg rabbits were fed a cholesterol diet for 16 and 28 weeks, and their aortic and coronary atherosclerosis was compared. Gross aortic lesion areas were significantly increased in female Tg rabbits at 28 weeks; however, pathological examination revealed that all the lesions of Tg rabbits fed a cholesterol diet for either 16 or 28 weeks were characterized by increased monocyte/macrophage accumulation and prominent lipid core formation compared with those of non‐Tg rabbits. Macrophages isolated from Tg rabbits exhibited higher infiltrative activity towards a chemoattractant, MCP‐1 in vitro and augmented capability of hydrolysing extracellular matrix in granulomatous tissue. Surprisingly, the lesions of Tg rabbits showed more advanced lesions with remarkable calcification in both aortas and coronary arteries. In conclusion, macrophage‐derived MMP‐9 facilitates the infiltration of monocyte/macrophages into the lesions thereby enhancing the progression of atherosclerosis. Increased accumulation of lesional macrophages may promote vascular calcification.
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Affiliation(s)
- Yajie Chen
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan
| | - Ahmed Bilal Waqar
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan
| | - Kazutoshi Nishijima
- Bioscience Education-Research Support Center, Akita University, Akita, Japan
| | - Bo Ning
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan.,School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China
| | - Shuji Kitajima
- Analytical Research Center for Experimental Sciences, Saga University, Saga, Japan
| | - Fumikazu Matsuhisa
- Analytical Research Center for Experimental Sciences, Saga University, Saga, Japan
| | - Lu Chen
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan
| | - Enqi Liu
- Research Institute of Atherosclerotic Disease and Laboratory Animal Center, Xi'an Jiaotong University School of Medicine, Xi'an, China
| | - Tomonari Koike
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Ying Yu
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Jifeng Zhang
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Yuqing Eugene Chen
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Huijun Sun
- Department of Pharmacology, Dalian Medical University, Dalian, China
| | - Jingyan Liang
- Research Center for Vascular Biology, School of Medicine, Yangzhou University, Yangzhou, China
| | - Jianglin Fan
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan.,School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China
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Allahverdian S, Ortega C, Francis GA. Smooth Muscle Cell-Proteoglycan-Lipoprotein Interactions as Drivers of Atherosclerosis. Handb Exp Pharmacol 2020; 270:335-358. [PMID: 33340050 DOI: 10.1007/164_2020_364] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In humans, smooth muscle cells (SMCs) are the main cell type in the artery medial layer, in pre-atherosclerotic diffuse thickening of the intima, and in all stages of atherosclerotic lesion development. SMCs secrete the proteoglycans responsible for the initial binding and retention of atherogenic lipoproteins in the artery intima, with this retention driving foam cell formation and subsequent stages of atherosclerosis. In this chapter we review current knowledge of the extracellular matrix generated by SMCs in medial and intimal arterial layers, their relationship to atherosclerotic lesion development and stabilization, how these findings correlate with mouse models of atherosclerosis, and potential therapies aimed at targeting the SMC matrix-lipoprotein interaction for atherosclerosis prevention.
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Affiliation(s)
- Sima Allahverdian
- Department of Medicine, Centre for Heart Lung Innovation, Providence Healthcare Research Institute, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Carleena Ortega
- Department of Medicine, Centre for Heart Lung Innovation, Providence Healthcare Research Institute, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Gordon A Francis
- Department of Medicine, Centre for Heart Lung Innovation, Providence Healthcare Research Institute, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
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Munjas J, Sopić M, Bogavac-Stanojević N, Kravljača M, Miljković M, Simić-Ogrizović S, Spasojević-Kalimanovska V, Jelić-Ivanović Z. Serum Resistin, Adenylate Cyclase-Associated Protein 1 Gene Expression, and Carotid Intima-Media Thickness in Patients with End-Stage Renal Disease and Healthy Controls. Cardiorenal Med 2019; 10:51-60. [PMID: 31722350 DOI: 10.1159/000503416] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 09/17/2019] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Human resistin is a proinflammatory cytokine with significant proatherogenic effects which acts through adenylyl cyclase-associated protein 1 (CAP1). Chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients have increased cardiovascular risk and resistin levels. Previous studies indicated resistin significance as a predictor of mortality in CKD. AIMS We sought to investigate plasma resistin levels, peripheral blood mononuclear cell (PBMC) resistin mRNA, and for the first time CAP1 mRNA levels in ESRD patients and healthy controls. We also sought to investigate the relation of resistin and CAP1 to carotid intima media thickness (CIMT), CD36 gene expression, and matrix metalloproteinase 9 (MMP-9) circulating levels in ESRD patients and healthy controls. METHODS This study included 33 patients with ESRD and 27 healthy controls. Resistin and MMP-9 levels were measured by ELISA. Resistin, CAP1, and CD36 PBMC mRNA were measured by quantitative PCR. RESULTS Our study showed that ESRD patients have significantly higher levels of circulatory resistin compared to healthy controls (p < 0.001), while there was no significant difference in resistin mRNA. A significant upregulation of CAP1 and CD36 was observed in the ESRD group (p < 0.001; p < 0.001). Resistin concentration correlated with CIMT in healthy controls (r = 0.512, p = 0.036), and with MMP-9 concentration in ESRD (r = 0.353, p = 0.044) and healthy controls (r = 0.463, p = 0.026). CAP1 correlated positively with CIMT (r = 0.464, p = 0.008) in ESRD, and with CD36 in healthy controls (r = 0.447, p = 0.022) and ESRD (r = 0.824, p < 0.001). CONCLUSION The obtained data suggest that high levels of circulating resistin acting upon cells with an upregulated CAP1 gene could contribute to the increased inflammation and accelerated atherosclerosis seen in CKD patients.
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Affiliation(s)
- Jelena Munjas
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Miron Sopić
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia,
| | | | - Milica Kravljača
- Department of Nephrology, Clinical Center of Serbia, Belgrade, Serbia
| | - Milica Miljković
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | | | | | - Zorana Jelić-Ivanović
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
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Song Z, Li H, Liang J, Xu Y, Zhu L, Ye X, Wu J, Li W, Xiong Q, Li S. Sulfated polysaccharide from Undaria pinnatifida stabilizes the atherosclerotic plaque via enhancing the dominance of the stabilizing components. Int J Biol Macromol 2019; 140:621-630. [PMID: 31445148 DOI: 10.1016/j.ijbiomac.2019.08.173] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 08/05/2019] [Accepted: 08/20/2019] [Indexed: 11/16/2022]
Abstract
The purpose of this study was to investigate the stable effect and mechanism of sulfated polysaccharide from Undaria pinnatifida (SPUP) on atherosclerotic plaque. The results showed that atherosclerotic plaques in the ApoE-/- mice of high-fat diet model group increased significantly without drug intervention. The content of vulnerable components (lipid, inflammatory macrophage) increased significantly, and the content of stability components (smooth muscle cell, collagen) reduced significantly. However, it could find that atherosclerotic plaque areas were decreased in a dose-dependent manner after SPUP intervention. SPUP could enhance the dominance of the stability components in plaque, and reduce the content of vulnerable component. Furthermore, SPUP could significantly reduce the matrix metalloprotein-9 content in atherosclerotic plaque. These results suggested that SPUP could stabilize atherosclerotic plaque by enhancing the dominance of the stability components content, reducing the vulnerability components content, and lowering the vulnerability index value.
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Affiliation(s)
- Zhuoyue Song
- School of Pharmaceutical Science, Mathematical Engineering Academy of Chinese Medicine, Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, PR China
| | - Hailun Li
- Department of Geriatric Medicine, Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an 223002, Jiangsu, PR China
| | - Jian Liang
- School of Pharmaceutical Science, Mathematical Engineering Academy of Chinese Medicine, Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, PR China
| | - Yingtao Xu
- School of Chinese Medicine, Shandong College of Traditional Chinese Medicine, Yantai 264199, Shangdong, PR China
| | - Lijun Zhu
- School of Pharmaceutical Science, Mathematical Engineering Academy of Chinese Medicine, Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, PR China
| | - Xianying Ye
- School of Pharmaceutical Science, Mathematical Engineering Academy of Chinese Medicine, Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, PR China
| | - Jun Wu
- School of Chinese Medicine, Shandong College of Traditional Chinese Medicine, Yantai 264199, Shangdong, PR China
| | - Wei Li
- School of Pharmaceutical Science, Mathematical Engineering Academy of Chinese Medicine, Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, PR China
| | - Qingping Xiong
- School of Pharmaceutical Science, Mathematical Engineering Academy of Chinese Medicine, Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, PR China; Jiangsu Provincial Key Laboratory of Palygorskite Science and Applied Technology, Huaiyin Institute of Technology, Huai'an 223003, Jiangsu, PR China.
| | - Shijie Li
- School of Pharmaceutical Science, Mathematical Engineering Academy of Chinese Medicine, Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, PR China.
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Cerofolini L, Fragai M, Luchinat C. Mechanism and Inhibition of Matrix Metalloproteinases. Curr Med Chem 2019; 26:2609-2633. [PMID: 29589527 DOI: 10.2174/0929867325666180326163523] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 03/06/2018] [Accepted: 03/06/2018] [Indexed: 01/02/2023]
Abstract
Matrix metalloproteinases hydrolyze proteins and glycoproteins forming the extracellular matrix, cytokines and growth factors released in the extracellular space, and membrane-bound receptors on the outer cell membrane. The pathological relevance of MMPs has prompted the structural and functional characterization of these enzymes and the development of synthetic inhibitors as possible drug candidates. Recent studies have provided a better understanding of the substrate preference of the different members of the family, and structural data on the mechanism by which these enzymes hydrolyze the substrates. Here, we report the recent advancements in the understanding of the mechanism of collagenolysis and elastolysis, and we discuss the perspectives of new therapeutic strategies for targeting MMPs.
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Affiliation(s)
- Linda Cerofolini
- Magnetic Resonance Center (CERM), University of Florence, and Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (CIRMMP), Via L. Sacconi 6, 50019 Sesto Fiorentino, Italy
| | - Marco Fragai
- Magnetic Resonance Center (CERM), University of Florence, and Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (CIRMMP), Via L. Sacconi 6, 50019 Sesto Fiorentino, Italy.,Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy
| | - Claudio Luchinat
- Magnetic Resonance Center (CERM), University of Florence, and Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (CIRMMP), Via L. Sacconi 6, 50019 Sesto Fiorentino, Italy.,Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy
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Zhou L, Wang Y, Wang K, Wang J, Ma A, Pan X. Potential therapeutic drugs for ischemic stroke based on bioinformatics analysis. Int J Neurosci 2019; 129:1098-1102. [PMID: 31387440 DOI: 10.1080/00207454.2019.1634072] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Ischemic stroke (IS) is a complex disease affected by various environmental factors, genetic factors and their interactions. Because genetic factors occupy an irreplaceable place in the pathogenesis of IS, the identification of genetic factors has become one of the hot spots in the current research. In the present study, we aimed to identify possible gene targets and relevant drug molecules in the pathogenesis of IS. Microarray dataset of GSE16561 was downloaded from Gene Expression Omnibus database. The differentially expressed genes (DEGs) between IS group and control group were obtained using limma package in R. Ground-Operation Simulation package in R language was used to cluster DEGs according to their biological process, cellular components and molecular functions with respect to the GO annotation. The DEGs were analyzed by Search Tool for the Retrieval of Interacting Genes online database and Cytoscape software to predict their interaction relationship. Finally, the DEGs were submitted to DGIdb dataset and related drug molecules were retrieved. 20 DEGs were identified from IS group including 1 downregulated and 19 upregulated genes. The function enrichment analysis revealed that the DEGs were enriched in three GO terms, mainly including inflammatory response, positive regulation of protein kinase activity and innate immune response. Finally, 10 drug molecules were identified from the DEGs. Our study identified some potential biological targets and drug molecules for the treatment of IS.
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Affiliation(s)
- Lingyan Zhou
- Department of Neurology , The Affiliated Hospital of Qingdao University , Qingdao , China
| | - Yuan Wang
- Department of Neurology , The Affiliated Hospital of Qingdao University , Qingdao , China
| | - Kun Wang
- Department of Neurology , The Affiliated Hospital of Qingdao University , Qingdao , China
| | - Jing Wang
- Department of Neurology , The Affiliated Hospital of Qingdao University , Qingdao , China
| | - Aijun Ma
- Department of Neurology , The Affiliated Hospital of Qingdao University , Qingdao , China
| | - Xudong Pan
- Department of Neurology , The Affiliated Hospital of Qingdao University , Qingdao , China
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Li C, Zhang Z, Peng Y, Gao H, Wang Y, Zhao J, Pan C. Plasma neutrophil gelatinase-associated lipocalin levels are associated with the presence and severity of coronary heart disease. PLoS One 2019; 14:e0220841. [PMID: 31387110 PMCID: PMC6684288 DOI: 10.1371/journal.pone.0220841] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 07/24/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE This study aimed to compare the levels of plasma neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase (MMP)-9, high-sensitivity C-reactive protein (hs-CRP), and interleukin (IL)-1β across different clinical presentations of coronary artery disease and to evaluate the relationship between those biomarkers and the severity of coronary artery lesions in patients without kidney disease. METHODS We examined 365 eligible patients who underwent coronary angiography. A total of 124 ST-segment elevation myocardial infarction (STEMI) patients, 117 stable angina pectoris (SAP) patients and 124 patients without atherosclerotic plaques were enrolled in the study. Plasma NGAL, MMP-9, hs-CRP, and IL-1β were measured in all patients using the enzyme-linked immunosorbent assay (ELISA) method. According to the SYNTAX score, the STEMI patients and SAP patients were divided into another set of 2 groups: a high score group (≥ 33, n = 29) and a low score group (<33, n = 212). The relationship between those biomarkers and the severity of coronary stenosis was examined by Spearman correlation analysis; the ability for NGAL to discriminate severe coronary stenosis was examined by receiver operating characteristic (ROC) curve; the influencing factors for the SYNTAX score were determined by logistic regression analysis. RESULTS Plasma NGAL, MMP-9, and hs-CRP levels in STEMI patients were higher than in the SAP patients and control subjects (P<0.05, respectively), and plasma NGAL and hs-CRP levels were significantly higher in the SAP patients than in control subjects (P<0.05, respectively), while plasma IL-1β was similar among the 3 groups (P>0.05, respectively). The SYNTAX score was positively related to NGAL (r = 0.363, P<0.001), MMP-9 (r = 0.377, P<0.001), and hs-CRP (r = 0.163, P<0.011); the SYNTAX score was not related to IL-1β (r = -0.043, P = 0.510). Plasma NGAL was positively related to MMP-9 (r = 0.601, P<0.001) and IL-1β (r = 0.159, P = 0.014). The area under the ROC curve for NGAL discriminating severe coronary stenosis was 0.838 (95% CI: 0.752-0.923, P<0.001), which was greater than that for MMP-9 [0.818, (95% CI: 0.724-0.912, P<0.001)], IL-1β [0.485, (95% CI: 0.369-0.601, P = 0.791)], and hs-CRP [0.607, (95% CI: 0.492-0.722, P = 0.061)]. Multivariate regression analysis showed that plasma NGAL levels were independently related to high SYNTAX scores [OR = 1.109, (95% CI: 1.104-1.114), P<0.001]. CONCLUSION Plasma NGAL, MMP-9, and hs-CRP levels in STEMI patients were higher than those in the SAP patients and control subjects. NGAL had a better ability to discriminate severe coronary stenosis than MMP-9, IL-1β, and hs-CRP. NGAL may be a novel biomarker to aid in risk stratification in coronary heart disease patients.
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Affiliation(s)
- Chao Li
- The First Clinical College of Lanzhou University, Lanzhou, Gansu, China
- Department of Cardiology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
- Gansu Key Laboratory of Cardiovascular Disease, Lanzhou, Gansu, China
| | - Zheng Zhang
- Department of Cardiology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
- * E-mail:
| | - Yu Peng
- Department of Cardiology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hanxiang Gao
- Department of Cardiology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yongxiang Wang
- Department of Cardiology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Jing Zhao
- Department of Cardiology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chenliang Pan
- Department of Cardiology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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Dambala K, Paschou SA, Michopoulos A, Siasos G, Goulis DG, Vavilis D, Tarlatzis BC. Biomarkers of Endothelial Dysfunction in Women With Polycystic Ovary Syndrome. Angiology 2019; 70:797-801. [DOI: 10.1177/0003319719840091] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of childbearing age. The criteria required for the diagnosis identify various phenotypes, with different reproductive, metabolic, and cardiovascular (CV) risk characteristics. Emerging evidence links adipocyte-secreted hormones as candidates in the pathogenesis of endothelial dysfunction in PCOS, independently of additional risk factors. The aim of this review was to collect, analyze, and qualitatively resynthesize evidence on biomarkers of endothelial dysfunction (visfatin, vascular endothelial growth factor [VEGF], matrix metalloproteinase 9 [MMP-9]) in women with PCOS. Women with PCOS exhibit (a) increased plasma visfatin concentrations compared with controls with a similar body mass index; (b) increased VEGF production along with chronic, mild inflammation; and (c) increased MMP-9 concentrations, which might be related to either excessive CV risk or abnormalities of ovarian extracellular matrix remodeling, multiple cyst formation, follicular atresia, and chronic anovulation. As PCOS has been associated with CV risk, early identification of endothelial dysfunction is clinically relevant.
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Affiliation(s)
- Kalliopi Dambala
- First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stavroula A. Paschou
- Division of Endocrinology and Diabetes, “Aghia Sophia” Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Alexandros Michopoulos
- First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Gerasimos Siasos
- First Department of Cardiology, Hippokration Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios G. Goulis
- First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios Vavilis
- First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Basil C. Tarlatzis
- First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Zaidi H, Byrkjeland R, Njerve IU, Åkra S, Solheim S, Arnesen H, Seljeflot I, Opstad TB. Effects of exercise training on markers of adipose tissue remodeling in patients with coronary artery disease and type 2 diabetes mellitus: sub study of the randomized controlled EXCADI trial. Diabetol Metab Syndr 2019; 11:109. [PMID: 31890043 PMCID: PMC6923919 DOI: 10.1186/s13098-019-0508-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 12/13/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Investigate effects of long-term exercise on the remodeling markers MMP-9, TIMP-1, EMMPRIN and Galectin-3 in combined type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) patients. Any associations between these biomarkers and glucometabolic variables were further assessed at baseline. METHODS 137 patients (age 41-81 years, 17.2% females) were included and randomized to a 12-months exercise program or to a control group. Fasting blood samples and subcutaneous adipose tissue (AT) samples were taken at inclusion and after 12-months. The intervention was a combination of aerobic and strength training for a minimum of 150 min per week. Circulating protein levels were measured by ELISA methods and RNA was extracted from AT and circulating leukocytes. Expression levels were relatively quantified by PCR. RESULTS After 12 months of intervention, both AT-expression and circulating levels of EMMPRIN were increased in the exercise group (p < 0.05, both) with significant difference in change between the two groups (p < 0.05 both). No significant effect was observed on MMP-9, TIMP-1 and Galectin-3. Levels of TIMP-1 (AT-expression and circulating) were significantly correlated to insulin, and HOMA2- after Bonferroni correction (p = 0.001, by 48 performed correlations). CONCLUSION The increase in levels of EMMPRIN after long-term exercise training, might indicate some degree of AT remodeling in these patients after 12-months of exercise, whether beneficial or not. The remodeling markers were to some extent associated with glucometabolic variables in our population with the combined disease.Trial registration clinicaltrials.gov, NCT01232608. Registered 2 November 2010.
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Affiliation(s)
- Hani Zaidi
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Nydalen, PB 4956, 0424 Oslo, Norway
- Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Rune Byrkjeland
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Nydalen, PB 4956, 0424 Oslo, Norway
- Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Ida U. Njerve
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Nydalen, PB 4956, 0424 Oslo, Norway
- Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway
| | - Sissel Åkra
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Nydalen, PB 4956, 0424 Oslo, Norway
- Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway
| | - Svein Solheim
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Nydalen, PB 4956, 0424 Oslo, Norway
- Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway
| | - Harald Arnesen
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Nydalen, PB 4956, 0424 Oslo, Norway
- Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Ingebjørg Seljeflot
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Nydalen, PB 4956, 0424 Oslo, Norway
- Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Trine B. Opstad
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Nydalen, PB 4956, 0424 Oslo, Norway
- Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
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Gargiulo S, Rossin D, Testa G, Gamba P, Staurenghi E, Biasi F, Poli G, Leonarduzzi G. Up-regulation of COX-2 and mPGES-1 by 27-hydroxycholesterol and 4-hydroxynonenal: A crucial role in atherosclerotic plaque instability. Free Radic Biol Med 2018; 129:354-363. [PMID: 30312760 DOI: 10.1016/j.freeradbiomed.2018.09.046] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 09/26/2018] [Accepted: 09/29/2018] [Indexed: 12/12/2022]
Abstract
Atherosclerosis is currently understood to be mainly the consequence of a complicated inflammatory process at the different stages of plaque development. Among the several inflammatory molecules involved, up-regulation of the functional cyclooxygenase 2/membrane-bound prostaglandin E synthase 1 (COX-2/mPGES-1) axis plays a key role in plaque development. Excessive production of oxidized lipids, following low-density lipoprotein (LDL) oxidation, is a characteristic feature of atherosclerosis. Among the oxidized lipids of LDLs, the oxysterol 27-hydroxycholesterol (27-OH) and the aldehyde 4-hydroxynonenal (HNE) substantially accumulate in the atherosclerotic plaque, contributing to its progression and instability through a variety of processes. This study shows that 27-OH and HNE promote up-regulation of both the inducible enzymes COX-2 and mPGES-1, leading to increased production of prostaglandin (PG) E2 and inducible nitric oxide synthase, and the subsequent release of nitric oxide in human promonocytic U937 cells. The study also examined the potential involvement of the functionally coupled COX-2/mPGES-1 in enhancing the production of certain pro-inflammatory cytokines and of matrix metalloproteinase 9 by U937 cells. This enhancement is presumably due to the induction of PGE2 synthesis, as a result of the up-regulation of the COX-2/mPGES-1, stimulated by the two oxidized lipids, 27-OH and HNE. Induction of PGE2 synthesis might thus be a mechanism of plaque instability and eventual rupture, contributing to matrix metalloproteinase production by activated macrophages.
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Affiliation(s)
- Simona Gargiulo
- Department of Clinical and Biological Sciences, School of Medicine, University of Turin, Orbassano, Torino, Italy
| | - Daniela Rossin
- Department of Clinical and Biological Sciences, School of Medicine, University of Turin, Orbassano, Torino, Italy
| | - Gabriella Testa
- Department of Clinical and Biological Sciences, School of Medicine, University of Turin, Orbassano, Torino, Italy
| | - Paola Gamba
- Department of Clinical and Biological Sciences, School of Medicine, University of Turin, Orbassano, Torino, Italy
| | - Erica Staurenghi
- Department of Clinical and Biological Sciences, School of Medicine, University of Turin, Orbassano, Torino, Italy
| | - Fiorella Biasi
- Department of Clinical and Biological Sciences, School of Medicine, University of Turin, Orbassano, Torino, Italy
| | - Giuseppe Poli
- Department of Clinical and Biological Sciences, School of Medicine, University of Turin, Orbassano, Torino, Italy
| | - Gabriella Leonarduzzi
- Department of Clinical and Biological Sciences, School of Medicine, University of Turin, Orbassano, Torino, Italy.
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Fan J, Chen Y, Yan H, Liu B, Wang Y, Zhang J, Chen YE, Liu E, Liang J. Genomic and Transcriptomic Analysis of Hypercholesterolemic Rabbits: Progress and Perspectives. Int J Mol Sci 2018; 19:3512. [PMID: 30413026 PMCID: PMC6274909 DOI: 10.3390/ijms19113512] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 11/04/2018] [Accepted: 11/05/2018] [Indexed: 12/22/2022] Open
Abstract
Rabbits (Oryctolagus cuniculus) are one of the most widely used animal models for the study of human lipid metabolism and atherosclerosis because they are more sensitive to a cholesterol diet than other experimental animals such as rodents. Currently, two hypercholesterolemic rabbit models are frequently used for atherosclerosis studies. One is a cholesterol-fed wild-type rabbit and the other is the Watanabe heritable hyperlipidemic (WHHL) rabbit, which is genetically deficient in low density lipoprotein (LDL) receptor function. Wild-type rabbits can be easily induced to develop severe hypercholesterolemia with a cholesterol-rich diet due to the marked increase in hepatically and intestinally derived remnant lipoproteins, called β-very low density lipoproteins (VLDL), which are rich in cholesteryl esters. WHHL rabbits are characterized by elevated plasma LDL levels on a standard chow diet, which resembles human familial hypercholesterolemia. Therefore, both rabbit models develop aortic and coronary atherosclerosis, but the elevated plasma cholesterol levels are caused by completely different mechanisms. In addition, cholesterol-fed rabbits but not WHHL rabbits exhibit different degrees of hepatosteatosis. Recently, we along with others have shown that there are many differentially expressed genes in the atherosclerotic lesions and livers of cholesterol-fed rabbits that are either significantly up- or down-regulated, compared with those in normal rabbits, including genes involved in the regulation of inflammation and lipid metabolism. Therefore, dietary cholesterol plays an important role not only in hypercholesterolemia and atherosclerosis but also in hepatosteatosis. In this review, we make an overview of the recent progress in genomic and transcriptomic analyses of hypercholesterolemic rabbits. These transcriptomic profiling data should provide novel insight into the relationship between hypercholesterolemia and atherosclerosis or hepatic dysfunction caused by dietary cholesterol.
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Affiliation(s)
- Jianglin Fan
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan.
- Department of Pathology, Xi'an Medical University, Xi'an 710021, China.
| | - Yajie Chen
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan.
| | - Haizhao Yan
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan.
| | - Baoning Liu
- Research Institute of Atherosclerotic Disease and Laboratory Animal Center, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, China.
| | - Yanli Wang
- Department of Pathology, Xi'an Medical University, Xi'an 710021, China.
| | - Jifeng Zhang
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
| | - Y Eugene Chen
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
| | - Enqi Liu
- Research Institute of Atherosclerotic Disease and Laboratory Animal Center, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, China.
| | - Jingyan Liang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225001, China.
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou 225001, China.
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou 225001, China.
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Arefieva TI, Filatova AY, Potekhina AV, Shchinova AM. Immunotropic Effects and Proposed Mechanism of Action for 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors (Statins). BIOCHEMISTRY (MOSCOW) 2018; 83:874-889. [PMID: 30208827 DOI: 10.1134/s0006297918080023] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Inhibitors of HMG-CoA reductase (statins) are the major group of lipid-lowering drugs. Along with hypocholesterolemic activity, statins exhibit anti-inflammatory and immunomodulatory properties that expand their clinical use, particularly, in the treatment of chronic inflammatory and autoimmune disorders. In this review, we critically analyze the data of statin effects on immune cells (e.g., monocytes and T cells) involved in the development of atherosclerosis and other chronic inflammatory diseases. We (i) discuss the properties of statins and routes of cell entry, as well as their major intracellular targets; (ii) evaluate the data on the effects of statins on the subset composition of circulatory monocytes, ability of monocytes to migrate to the site of inflammation (cell motility and expression of adhesion molecules and chemokine receptors), production of cytokines, matrix metalloproteinases, and reactive oxygen species by monocytes/macrophages, and antigen-presenting activity in peripheral blood monocyte-derived dendritic cells; and (iii) summarize the data on the regulation of proliferation and differentiation of various CD4+ T cell subsets (type 1/2/17 helper T cells and regulatory T cells) by statins.
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Affiliation(s)
- T I Arefieva
- National Medical Research Center of Cardiology, Ministry of Health of the Russian Federation, Moscow, 121552, Russia.,Kurchatov Institute National Research Center Complex, Moscow, 123182, Russia
| | - A Yu Filatova
- National Medical Research Center of Cardiology, Ministry of Health of the Russian Federation, Moscow, 121552, Russia.
| | - A V Potekhina
- National Medical Research Center of Cardiology, Ministry of Health of the Russian Federation, Moscow, 121552, Russia
| | - A M Shchinova
- National Medical Research Center of Cardiology, Ministry of Health of the Russian Federation, Moscow, 121552, Russia
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Zielinska-Turek J, Dorobek M, Turek G, Barcikowska-Kotowicz M. MMP-9 and/or TIMP as predictors of ischaemic stroke in patients with symptomatic and asymptomatic atherosclerotic stenosis of carotid artery treated by stenting or endarterectomy – A review. Neurol Neurochir Pol 2018; 52:555-561. [DOI: 10.1016/j.pjnns.2018.05.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 05/21/2018] [Accepted: 05/23/2018] [Indexed: 11/28/2022]
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Chen GZ, Ke Y, Qin K, Dong MQ, Zeng SJ, Lin XF, Zhan SQ, Tang K, Peng C, Ding XW, Zhou D. Analysis of the Expression of Angioarchitecture-related Factors in Patients with Cerebral Arteriovenous Malformation. Chin Med J (Engl) 2018; 130:2465-2472. [PMID: 29052569 PMCID: PMC5684641 DOI: 10.4103/0366-6999.216413] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background: Cerebral arteriovenous malformation (cAVM) is a type of vascular malformation associated with vascular remodeling, hemodynamic imbalance, and inflammation. We detected four angioarchitecture-related cytokines to make a better understanding of the potential aberrant signaling in the pathogenesis of cAVM and found useful proteins in predicting the risk of cerebral hemorrhage. Methods: Immunohistochemical analysis was conducted on specimens from twenty patients with cAVM diagnosed via magnetic resonance imaging and digital subtraction angiography and twenty primary epilepsy controls using antibodies against vascular endothelial growth factor receptor-2 (VEGFR-2), matrix metalloproteinase-9 (MMP-9), vascular cell adhesion molecule (VCAM-1), and endothelial nitric oxide synthase (eNOS). Western blotting and real-time fluorescent quantitative polymerase chain reaction (PCR) were performed to determine protein and mRNA expression levels. Student's t-test was used for statistical analysis. Results: VEGFR-2, MMP-9, VCAM-1, and eNOS expression levels increased in patients with cAVM compared with those in normal cerebral vascular tissue, as determined by immunohistochemical analysis. In addition, Western blotting and real-time PCR showed that the protein and mRNA expression levels of VEGFR-2, MMP-9, VCAM-1, and eNOS were higher in the cAVM group than in the control group, all the differences mentioned were statistically significant (P < 0.05). Conclusions: VEGFR-2, MMP-9, VCAM-1, and eNOS are upregulated in patients with cAVM and might play important roles in angiogenesis, vascular remodeling, and migration in patients with cAVM. MMP-9, VEGFR-2, VCAM-1, and eNOS might be potential excellent group proteins in predicting the risk of cerebral hemorrhage at arteriovenous malformation.
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Affiliation(s)
- Guang-Zhong Chen
- Department of Neurosurgery, Guangdong General Hospital, Institute of Neuroscience, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
| | - Yu Ke
- Department of Biomedical Engineering, Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China
| | - Kun Qin
- Department of Neurosurgery, Guangdong General Hospital, Institute of Neuroscience, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
| | - Meng-Qi Dong
- Department of Neurosurgery, Guangdong General Hospital, Institute of Neuroscience, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
| | - Shao-Jian Zeng
- Department of Neurosurgery, Guangdong General Hospital, Institute of Neuroscience, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
| | - Xiao-Feng Lin
- Department of Neurosurgery, Guangdong General Hospital, Institute of Neuroscience, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
| | - Sheng-Quan Zhan
- Department of Neurosurgery, Guangdong General Hospital, Institute of Neuroscience, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
| | - Kai Tang
- Department of Neurosurgery, Guangdong General Hospital, Institute of Neuroscience, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
| | - Chao Peng
- Department of Neurosurgery, Guangdong General Hospital, Institute of Neuroscience, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
| | - Xiao-Wen Ding
- Department of Neurosurgery, Guangdong General Hospital, Institute of Neuroscience, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
| | - Dong Zhou
- Department of Neurosurgery, Guangdong General Hospital, Institute of Neuroscience, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
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Functional Assessment of Intermediate Vascular Disease. BIOMED RESEARCH INTERNATIONAL 2018; 2018:7619092. [PMID: 29850561 PMCID: PMC5925208 DOI: 10.1155/2018/7619092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 09/12/2017] [Accepted: 01/28/2018] [Indexed: 11/19/2022]
Abstract
Interventional treatment in various vascular beds has advanced tremendously. However, there are several problems to be considered. We searched the literature and tried to analyze major parts of it. One is safety and applicability of coronary proven methods in other vascular beds. An unresolved problem is the functional assessment of intermediate lesions, as far as various target organs have quite different circulation from the coronary one and the functional tests should be modified in order to be applicable and meaningful. In the majority of the acute vascular syndromes, the culprit lesion is of intermediate size on visual assessment. On the other hand, a procedurally successfully managed high-degree stenosis is not always followed by clinical and prognostic benefit. In vascular beds, where collateral network naturally exists, the readings from the functional assessment are complicated and thus the decision for interventional treatment is even more difficult. Here come into help the functional assessment and imaging with IVUS, OCT, high-resolution MRI, and contrast enhanced CT or SPECT. The focus of the current review is on the functional assessment of intermediate stenosis in other vascular beds, unlike the coronary arteries.
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