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Huang X, Jiang F, Ma Y, Zhu K, Wang Z, Hua Z, Yu J, Zhang L. A bibliometric analysis of endoplasmic reticulum stress and atherosclerosis. Front Physiol 2024; 15:1392454. [PMID: 38938744 PMCID: PMC11210825 DOI: 10.3389/fphys.2024.1392454] [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: 03/25/2024] [Accepted: 05/24/2024] [Indexed: 06/29/2024] Open
Abstract
The mechanisms underlying the occurrence and development of atherosclerosis (AS) are diverse, among which endoplasmic reticulum stress (ERS) is an important mechanism that should not be overlooked. However, up to now, there has been no bibliometric study on the relationship between ERS and AS. To understand the research progress in ERS and AS, this paper conducted a statistical analysis of publications in this field using bibliometrics. A total of 1,035 records were retrieved from the Web of Science Core Collection. CiteSpace, VOSviewer, and the R package "bibliometric" were used to analyze the spatiotemporal distribution, countries, authors, institutions, journals, references, and keywords of the literature, and to present the basic information of this field through visualized maps, as well as determine the collaboration relationships among researchers in this field. This field has gradually developed and stabilized over the past 20 years. The current research hotspots in this field mainly include the relationship between ERS and AS-related cells, the mechanisms by which ERS promotes AS, related diseases, and associated cytokines, etc. Vascular calcification, endothelial dysfunction, NLRP3 inflammasome, and heart failure represent the frontier research in this field and are becoming new research hotspots. It is hoped that this study will provide new insights for research and clinical work in the field of ERS and AS.
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Affiliation(s)
- Xinyu Huang
- Shandong University of Traditional Chinese Medicine, Shandon, China
| | - Feng Jiang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandon, China
| | - Yongbo Ma
- Shandong University of Traditional Chinese Medicine, Shandon, China
| | - Kunpeng Zhu
- Shandong University of Traditional Chinese Medicine, Shandon, China
| | - Zhenyuan Wang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandon, China
| | - Zhen Hua
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandon, China
| | - Jie Yu
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandon, China
| | - Lei Zhang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandon, China
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Shao X, Hou X, Zhang X, Zhang R, Zhu R, Qi H, Zheng J, Guo X, Feng R. Integrated single-cell RNA-seq analysis reveals the vital cell types and dynamic development signature of atherosclerosis. Front Physiol 2023; 14:1118239. [PMID: 37089432 PMCID: PMC10117136 DOI: 10.3389/fphys.2023.1118239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 03/06/2023] [Indexed: 04/03/2023] Open
Abstract
Introduction: In the development of atherosclerosis, the remodeling of blood vessels is a key process involving plaque formation and rupture. So far, most reports mainly believe that macrophages, smooth muscle cells, and endothelial cells located at the intima and media of artery play the key role in this process. Few studies had focused on whether fibroblasts located at adventitia are involved in regulating disease process.Methods and results: In this study, we conducted in-depth analysis of single-cell RNA-seq data of the total of 18 samples from healthy and atherosclerotic arteries. This study combines several analysis methods including transcription regulator network, cell-cell communication network, pseudotime trajectory, gene set enrichment analysis, and differential expression analysis. We found that SERPINF1 is highly expressed in fibroblasts and is involved in the regulation of various signaling pathways.Conclusion: Our research reveals a potential mechanism of atherosclerosis, SERPINF1 regulates the formation and rupture of plaques through the Jak-STAT signaling pathway, which may provide new insights into the pathological study of disease. Moreover, we suggest that SRGN and IGKC as potential biomarkers for unstable arterial plaques.
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Affiliation(s)
- Xiuli Shao
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, China
| | - Xiuyang Hou
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, China
| | - Xiaolin Zhang
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, China
| | - Ruijia Zhang
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, China
| | - Rongli Zhu
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, China
| | - He Qi
- Department of Medical Biotechnology, Liaoning Vocational College of Medicine, Shenyang, China
| | - Jianling Zheng
- Department of Medical Biotechnology, Liaoning Vocational College of Medicine, Shenyang, China
| | - Xiaoling Guo
- Center of Scientific Research, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Rui Feng
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, China
- *Correspondence: Rui Feng,
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Maity J, Dey T, Banerjee A, Chattopadhyay A, Das AR, Bandyopadhyay D. Melatonin ameliorates myocardial infarction in obese diabetic individuals: The possible involvement of macrophage apoptotic factors. J Pineal Res 2023; 74:e12847. [PMID: 36456538 DOI: 10.1111/jpi.12847] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/14/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022]
Abstract
In recent days, the hike in obesity-mediated epidemics across the globe and the prevalence of obesity-induced cardiovascular disease has become one of the chief grounds for morbidity and mortality. This epidemic-driven detrimental events in the cardiac tissues start with the altered distribution and metabolism pattern of high-density lipoprotein and low-density lipoprotein (LDL) leading to cholesterol (oxidized LDL) deposition on the arterial wall and atherosclerotic plaque generation, followed by vascular spasms and infarction. Subsequently, obesity-triggered metabolic malfunctions induce free radical generation which may further trigger pro-inflammatory signaling and nuclear factor kappa-light-chain-enhancer of activated B cells transcriptional factor, thus inducing interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase. This terrifying cardiomyopathy can be further aggravated in type 2 diabetes mellitus, thereby making obese diabetic patients prone toward the development of myocardial infarction (MI) or stroke in comparison to their nondiabetic counterparts. The accelerated oxidative stress and pro-inflammatory response induced cardiomyocyte hypertrophy, followed by apoptosis in obese diabetic individuals, causing progression of athero-thrombotic vascular disease. Being an efficient antioxidative and anti-inflammatory indolamine, melatonin effectively inhibits lipid peroxidation, pro-inflammatory reactions, thereby resolving free radical-induced myocardial damages along with maintaining antioxidant reservoir to preserve cardiovascular integrity. Prolonged melatonin treatment maintains balanced body weight and serum total cholesterol concentration by inhibiting cholesterol synthesis and promoting cholesterol catabolism. Additionally, melatonin promotes macrophage polarization toward the anti-inflammatory state, providing a proper shield during the recovery period. Therefore, the protective role of melatonin in maintaining the lipid metabolism homeostasis and blocking the atherosclerotic plaque rupture could be targeted as the possible therapeutic strategy for the management of obesity-induced acute MI. This review aimed at orchestrating the efficacy of melatonin in ameliorating irrevocable oxidative cardiovascular damage induced by the obesity-diabetes correlation.
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Affiliation(s)
- Juin Maity
- Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, Kolkata, India
| | - Tiyasa Dey
- Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, Kolkata, India
| | - Adrita Banerjee
- Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, Kolkata, India
| | | | - Asish R Das
- Department of Chemistry, University of Calcutta, Kolkata, India
| | - Debasish Bandyopadhyay
- Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, Kolkata, India
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Moutan Cortex Extract Modulates Macrophage Activation via Lipopolysaccharide-Induced Calcium Signaling and ER Stress-CHOP Pathway. Int J Mol Sci 2023; 24:ijms24032062. [PMID: 36768384 PMCID: PMC9916843 DOI: 10.3390/ijms24032062] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
Moutan Cortex, Paeonia suffruticosa root, has long been used as a medicine for the treatment of inflammatory diseases. The aim of this study was to evaluate the modulative properties of Moutan Cortex water extract (CP) on endoplasmic reticulum (ER) stress-related macrophage activation via the calcium-CHOP pathway. RAW 264.7 mouse macrophages were activated by lipopolysaccharide (LPS), and the levels of various inflammatory mediators from RAW 264.7 were evaluated. The multiplex cytokine assay was used to investigate both cytokines and growth factors, and RT-PCR was used to investigate the expressions of inflammation-related genes, such as CHOP. Data represent the levels of NO and cytosolic calcium in LPS-stimulated RAW 264.7 were significantly inhibited by CP as well as hydrogen peroxide (p < 0.05). Minutely, NO production in LPS-stimulated RAW 264.7 incubated with CP at concentrations of 25, 50, 100, and 200 µg/mL for 24 h was 97.32 ± 1.55%, 95.86 ± 2.26%, 94.64 ± 1.83%, and 92.69 ± 2.31% of the control value (LPS only), respectively (p < 0.05). Calcium release in LPS-stimulated RAW 264.7 incubated with CP at concentrations of 25, 50, 100, and 200 µg/mL for 18 h was 95.78 ± 1.64%, 95.41 ± 1.14%, 94.54 ± 2.76%, and 90.89 ± 3.34% of the control value, respectively (p < 0.05). Hydrogen peroxide production in LPS-stimulated RAW 264.7 incubated with CP at concentrations of 25, 50, 100, and 200 µg/mL for 24 h was 79.15 ± 7.16%, 63.83 ± 4.03%, 46.27 ± 4.38%, and 40.66 ± 4.03% of the control value, respectively (p < 0.05). It is interesting that the production of IL-6, TNF-α, G-CSF, MIP-1α, MIP-2, and M-CSF in LPS-stimulated RAW 264.7 were significantly inhibited by CP (p < 0.05), while the production of LIX, LIF, RANTES, and MIP-1β showed a meaningful decrease. CP at concentrations of 25, 50, 100, and 200 µg/mL significantly reduced the transcription of Chop, Camk2α, NOS, STAT1, STAT3, Ptgs2, Jak2, c-Jun, Fas, c-Fos, TLR3, and TLR9 in LPS-stimulated RAW 264.7 (p < 0.05). CP at concentrations of 25, 50, and 100 µg/mL significantly reduced the phosphorylation of STAT3, p38 MAPK, and IκB-α in LPS-stimulated RAW 264.7 (p < 0.05). These results suggest that CP might modulate macrophage activation via LPS-induced calcium signaling and the ER stress-CHOP pathway.
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Jiang Y, Qian HY. Transcription factors: key regulatory targets of vascular smooth muscle cell in atherosclerosis. Mol Med 2023; 29:2. [PMID: 36604627 PMCID: PMC9817296 DOI: 10.1186/s10020-022-00586-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 12/05/2022] [Indexed: 01/07/2023] Open
Abstract
Atherosclerosis (AS), leading to gradual occlusion of the arterial lumen, refers to the accumulation of lipids and inflammatory debris in the arterial wall. Despite therapeutic advances over past decades including intervention or surgery, atherosclerosis is still the most common cause of cardiovascular diseases and the main mechanism of death and disability worldwide. Vascular smooth muscle cells (VSMCs) play an imperative role in the occurrence of atherosclerosis and throughout the whole stages. In the past, there was a lack of comprehensive understanding of VSMCs, but the development of identification technology, including in vivo single-cell sequencing technology and lineage tracing with the CreERT2-loxP system, suggests that VSMCs have remarkable plasticity and reevaluates well-established concepts about the contribution of VSMCs. Transcription factors, a kind of protein molecule that specifically recognizes and binds DNA upstream promoter regions or distal enhancer DNA elements, play a key role in the transcription initiation of the coding genes and are necessary for RNA polymerase to bind gene promoters. In this review, we highlight that, except for environmental factors, VSMC genes are transcriptionally regulated through complex interactions of multiple conserved cis-regulatory elements and transcription factors. In addition, through a series of transcription-related regulatory processes, VSMCs could undergo phenotypic transformation, proliferation, migration, calcification and apoptosis. Finally, enhancing or inhibiting transcription factors can regulate the development of atherosclerotic lesions, and the downstream molecular mechanism of transcriptional regulation has also been widely studied.
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Affiliation(s)
- Yu Jiang
- grid.506261.60000 0001 0706 7839Center for Coronary Heart Disease, Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Rd, Beijing, 100037 China
| | - Hai-Yan Qian
- grid.506261.60000 0001 0706 7839Center for Coronary Heart Disease, Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Rd, Beijing, 100037 China
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Kawai K, Vozenilek AE, Kawakami R, Sato Y, Ghosh SKB, Virmani R, Finn AV. Understanding the role of alternative macrophage phenotypes in human atherosclerosis. Expert Rev Cardiovasc Ther 2022; 20:689-705. [PMID: 35942866 DOI: 10.1080/14779072.2022.2111301] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
INTRODUCTION Atherosclerosis-based ischemic heart disease is still the primary cause of death throughout the world. Over the past decades there has been no significant changes in the therapeutic approaches to atherosclerosis, which are mainly based on lipid lowering therapies and management of comorbid conditions such as diabetes and hypertension. The involvement of macrophages in atherosclerosis has been recognized for decades. More recently, a more detailed and sophisticated understanding of their various phenotypes and roles in the atherosclerotic process has been recognized. This new data is revealing how specific subtypes of macrophage-induced inflammation may have distinct effects on atherosclerosis progression and may provide new approaches for treatment, based upon targeting of specific macrophage subtypes. AREAS COVERED We will comprehensively review the spectrum of macrophage phenotypes and how they contribute to atherosclerotic plaque development and progression. EXPERT OPINION Various signals derived from atherosclerotic lesions drive macrophages into complex subsets with different gene expression profiles, phenotypes, and functions, not all of which are understood. Macrophage phenotypes include those that enhance, heal, and regress the atherosclerotic lesions though various mechanisms. Targeting of specific macrophage phenotypes may provide a promising and novel approach to prevent atherosclerosis progression.
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Affiliation(s)
- Kenji Kawai
- Department of Cardiovascular Pathology, CVPath Institute, Gaithersburg, MD, USA
| | - Aimee E Vozenilek
- Department of Cardiovascular Pathology, CVPath Institute, Gaithersburg, MD, USA
| | - Rika Kawakami
- Department of Cardiovascular Pathology, CVPath Institute, Gaithersburg, MD, USA
| | - Yu Sato
- Department of Cardiovascular Pathology, CVPath Institute, Gaithersburg, MD, USA
| | | | - Renu Virmani
- Department of Cardiovascular Pathology, CVPath Institute, Gaithersburg, MD, USA
| | - Aloke V Finn
- Department of Cardiovascular Pathology, CVPath Institute, Gaithersburg, MD, USA.,University of Maryland, School of Medicine, Baltimore, MD, USA
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Zhang Z, Liu F, Chen W, Liao Z, Zhang W, Zhang B, Liang H, Chu L, Zhang Z. The importance of N6-methyladenosine modification in tumor immunity and immunotherapy. Exp Hematol Oncol 2022; 11:30. [PMID: 35590394 PMCID: PMC9118853 DOI: 10.1186/s40164-022-00281-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 04/16/2022] [Indexed: 12/31/2022] Open
Abstract
As the most common and abundant RNA modification in eukaryotic cells, N6-methyladenosine (m6A) modification plays an important role in different stages of tumor. m6A can participate in the regulation of tumor immune escape, so as to enhance the monitoring of tumor by the immune system and reduce tumorgenesis. m6A can also affect the tumor progression by regulating the immune cell responses to tumor in tumor microenvironment. In addition, immunotherapy has become the most popular method for the treatment of cancer, in which targets such as immune checkpoints are also closely associated with m6A. This review discusses the roles of N6-methyladenosine modification in tumor immune regulation, their regulatory mechanism, and the prospect of immunotherapy.
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Affiliation(s)
- Ze Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China
| | - Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China
| | - Wei Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China
| | - Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China
| | - Wanguang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China
| | - Liang Chu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China.
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China.
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Camponogara C, Oliveira SM. Are TRPA1 and TRPV1 channel-mediated signalling cascades involved in UVB radiation-induced sunburn? ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2022; 92:103836. [PMID: 35248760 DOI: 10.1016/j.etap.2022.103836] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/09/2022] [Accepted: 02/28/2022] [Indexed: 06/14/2023]
Abstract
Burn injuries are underappreciated injuries associated with substantial morbidity and mortality. Overexposure to ultraviolet (UV) radiation has dramatic clinical effects in humans and is a significant public health concern. Although the mechanisms underlying UVB exposure are not fully understood, many studies have made substantial progress in the pathophysiology of sunburn in terms of its molecular aspects in the last few years. It is well established that the transient receptor potential ankyrin 1 (TRPA1), and vanilloid 1 (TRPV1) channels modulate the inflammatory, oxidative, and proliferative processes underlying UVB radiation exposure. However, it is still unknown which mechanisms underlying TRPV1/A1 channel activation are elicited in sunburn induced by UVB radiation. Therefore, in this review, we give an overview of the TRPV1/A1 channel-mediated signalling cascades that may be involved in the pathophysiology of sunburn induced by UVB radiation. These data will undoubtedly help to explain the various features of sunburn and contribute to the development of novel therapeutic approaches to better treat it.
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Affiliation(s)
- Camila Camponogara
- Graduated Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Sara Marchesan Oliveira
- Graduated Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil; Department of Biochemistry and Molecular Biology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil.
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Jiang XX, Bian W, Zhu YR, Wang Z, Ye P, Gu Y, Zhang H, Zuo G, Li X, Zhu L, Liu Z, Sun C, Chen SL, Zhang DM. Targeting the KCa3.1 channel suppresses diabetes-associated atherosclerosis via the STAT3/CD36 axis. Diabetes Res Clin Pract 2022; 185:109776. [PMID: 35149165 DOI: 10.1016/j.diabres.2022.109776] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 01/21/2022] [Accepted: 02/07/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND In diet-induced arterial atherosclerosis, increased KCa3.1 channel was associated with atherosclerotic plaque progression and instability. Macrophages are involved in the formation of atherosclerotic plaques, and the release of inflammatory cytokines and oxygen free radicals promotes plaque progression. However, whether the macrophage KCa3.1 channel facilitates diabetes-accelerated atherosclerosis is still unclear. This study investigated atherosclerotic plaque in ApoE-/- mice regulated by the KCa3.1 channel. METHODS AND RESULTS In vivo, blocking KCa3.1channel inhibit the development of the atherosclerotic lesion in diabetic ApoE-/- mice fed with a high-fat diet. In vitro, upregulation of KCa3.1 channel level occurred in RAW264.7 cells treated with HG plus ox-LDL in a time-dependent manner. Blocking KCa3.1 significantly reduced the uptake of ox-LDL in mice peritoneal macrophages. Further studies indicated the KCa3.1 siRNA and TRAM-34 (KCa3.1 inhibitor) attenuated the scavenger receptor CD36 expression via inhibiting STAT3 phosphorylation. CONCLUSION Blockade of macrophage KCa3.1 channel inhibit cellular oxidized low-density lipoprotein accumulation and decrease proinflammation factors expression via STAT3/CD36 axis. This study provided a novel therapeutic target to reduce the risk of atherosclerosis development in diabetic patients.
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Affiliation(s)
- Xiao-Xin Jiang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China
| | - Weikang Bian
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China
| | - Yan-Rong Zhu
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China
| | - Zhicheng Wang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China
| | - Peng Ye
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China
| | - Yue Gu
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China
| | - Hongsong Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China
| | - Guangfeng Zuo
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China
| | - Xiaobo Li
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China
| | - Linlin Zhu
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China
| | - Zhizhong Liu
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China
| | - Chongxiu Sun
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China.
| | - Shao-Liang Chen
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China.
| | - Dai-Min Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China; Department of Cardiology, Sir Run Run Hospital, Nanjing Medical University, No. 109 Longmian Road, Nanjing 211166, PR China.
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Guan YH, Wang N, Deng ZW, Chen XG, Liu Y. Exploiting autophagy-regulative nanomaterials for activation of dendritic cells enables reinforced cancer immunotherapy. Biomaterials 2022; 282:121434. [DOI: 10.1016/j.biomaterials.2022.121434] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 01/15/2022] [Accepted: 02/17/2022] [Indexed: 02/07/2023]
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11
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La Manna S, De Benedictis I, Marasco D. Proteomimetics of Natural Regulators of JAK-STAT Pathway: Novel Therapeutic Perspectives. Front Mol Biosci 2022; 8:792546. [PMID: 35047557 PMCID: PMC8762217 DOI: 10.3389/fmolb.2021.792546] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 11/29/2021] [Indexed: 12/16/2022] Open
Abstract
The JAK-STAT pathway is a crucial cellular signaling cascade, including an intricate network of Protein-protein interactions (PPIs) responsible for its regulation. It mediates the activities of several cytokines, interferons, and growth factors and transduces extracellular signals into transcriptional programs to regulate cell growth and differentiation. It is essential for the development and function of both innate and adaptive immunities, and its aberrant deregulation was highlighted in neuroinflammatory diseases and in crucial mechanisms for tumor cell recognition and tumor-induced immune escape. For its involvement in a multitude of biological processes, it can be considered a valuable target for the development of drugs even if a specific focus on possible side effects associated with its inhibition is required. Herein, we review the possibilities to target JAK-STAT by focusing on its natural inhibitors as the suppressor of cytokine signaling (SOCS) proteins. This protein family is a crucial checkpoint inhibitor in immune homeostasis and a valuable target in immunotherapeutic approaches to cancer and immune deficiency disorders.
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Affiliation(s)
| | | | - Daniela Marasco
- Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Farahi L, Sinha SK, Lusis AJ. Roles of Macrophages in Atherogenesis. Front Pharmacol 2021; 12:785220. [PMID: 34899348 PMCID: PMC8660976 DOI: 10.3389/fphar.2021.785220] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/04/2021] [Indexed: 12/18/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory disease that may ultimately lead to local proteolysis, plaque rupture, and thrombotic vascular disease, resulting in myocardial infarction, stroke, and sudden cardiac death. Circulating monocytes are recruited to the arterial wall in response to inflammatory insults and differentiate into macrophages which make a critical contribution to tissue damage, wound healing, and also regression of atherosclerotic lesions. Within plaques, macrophages take up aggregated lipoproteins which have entered the vessel wall to give rise to cholesterol-engorged foam cells. Also, the macrophage phenotype is influenced by various stimuli which affect their polarization, efferocytosis, proliferation, and apoptosis. The heterogeneity of macrophages in lesions has recently been addressed by single-cell sequencing techniques. This article reviews recent advances regarding the roles of macrophages in different stages of disease pathogenesis from initiation to advanced atherosclerosis. Macrophage-based therapies for atherosclerosis management are also described.
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Affiliation(s)
- Lia Farahi
- Monoclonal Antibody Research Center, Avicenna Research Institute, Tehran, Iran
| | - Satyesh K. Sinha
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Aldons J. Lusis
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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13
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Al‐Ahmadi W, Webberley TS, Joseph A, Harris F, Chan Y, Alotibi R, Williams JO, Alahmadi A, Decker T, Hughes TR, Ramji DP. Pro-atherogenic actions of signal transducer and activator of transcription 1 serine 727 phosphorylation in LDL receptor deficient mice via modulation of plaque inflammation. FASEB J 2021; 35:e21892. [PMID: 34569651 PMCID: PMC9549671 DOI: 10.1096/fj.202100571rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 08/11/2021] [Accepted: 08/17/2021] [Indexed: 11/21/2022]
Abstract
Atherosclerosis is a chronic inflammatory disorder of the vasculature regulated by cytokines. We have previously shown that extracellular signal-regulated kinase-1/2 (ERK1/2) plays an important role in serine 727 phosphorylation of signal transducer and activator of transcription-1 (STAT1) transactivation domain, which is required for maximal interferon-γ signaling, and the regulation of modified LDL uptake by macrophages in vitro. Unfortunately, the roles of ERK1/2 and STAT1 serine 727 phosphorylation in atherosclerosis are poorly understood and were investigated using ERK1 deficient mice (ERK2 knockout mice die in utero) and STAT1 knock-in mice (serine 727 replaced by alanine; STAT1 S727A). Mouse Atherosclerosis RT² Profiler PCR Array analysis showed that ERK1 deficiency and STAT1 S727A modification produced significant changes in the expression of 18 and 49 genes, respectively, in bone marrow-derived macrophages, with 17 common regulated genes that included those that play key roles in inflammation and cell migration. Indeed, ERK1 deficiency and STAT1 S727A modification attenuated chemokine-driven migration of macrophages with the former also impacting proliferation and the latter phagocytosis. In LDL receptor deficient mice fed a high fat diet, both ERK1 deficiency and STAT1 S727A modification produced significant reduction in plaque lipid content, albeit at different time points. The STAT1 S727A modification additionally caused a significant reduction in plaque content of macrophages and CD3 T cells and diet-induced cardiac hypertrophy index. In addition, there was a significant increase in plasma IL-2 levels and a trend toward increase in plasma IL-5 levels. These studies demonstrate important roles of STAT1 S727 phosphorylation in particular in the regulation of atherosclerosis-associated macrophage processes in vitro together with plaque lipid content and inflammation in vivo, and support further assessment of its therapeutical potential.
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Affiliation(s)
| | | | - Alex Joseph
- Cardiff School of BiosciencesCardiff UniversityCardiffUK
| | - Ffion Harris
- Cardiff School of BiosciencesCardiff UniversityCardiffUK
| | - Yee‐Hung Chan
- Cardiff School of BiosciencesCardiff UniversityCardiffUK
| | - Reem Alotibi
- Cardiff School of BiosciencesCardiff UniversityCardiffUK
| | | | - Alaa Alahmadi
- Cardiff School of BiosciencesCardiff UniversityCardiffUK
| | - Thomas Decker
- Department of Microbiology and ImmunologyMax F. Perutz LaboratoriesUniversity of ViennaViennaAustria
| | - Timothy R. Hughes
- Systems Immunity Research InstituteSchool of MedicineCardiff UniversityCardiffUK
| | - Dipak P. Ramji
- Cardiff School of BiosciencesCardiff UniversityCardiffUK
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14
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Wang M, Liu F, Fang B, Huo Q, Yang Y. Proteome-scale profiling reveals MAFF and MAFG as two novel key transcription factors involved in palmitic acid-induced umbilical vein endothelial cell apoptosis. BMC Cardiovasc Disord 2021; 21:448. [PMID: 34535081 PMCID: PMC8447594 DOI: 10.1186/s12872-021-02246-5] [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: 09/15/2020] [Accepted: 09/08/2021] [Indexed: 12/17/2022] Open
Abstract
Background Vascular endothelial cell apoptosis is the leading risk factor of atherosclerosis (AS). The purpose of our study was to use a new generation high-throughput transcription factor (TF) detection method to identify novel key TFs in vascular endothelial cell apoptosis induced by palmitic acid (PA). Methods Human umbilical vein endothelial cells (HUVECs) were treated with 0, 300, or 500 µM PA. Candidate TFs in the three groups were identified by differential expression, pathway enrichment, Western Blot (WB), and RT-qPCR analyses. Apoptosis was assessed by fluorescence-activated cell sorting (FACS) using FITC-annexin V and propidium iodide staining. Results We established a HUVEC apoptosis model to simulate the process of atherosclerosis onset and identified 51 significant TFs. of the 51 TFs, v-maf musculoaponeurotic fibrosarcoma oncogene family protein G (MAFG) and v-maf musculoaponeurotic fibrosarcoma oncogene family protein F (MAFF), were matched to known AS signalling pathways and were validated by WB and RT-qPCR analyses in our study. Overexpression of MAFG or MAFF in HUVECs significantly inhibited PA-induced early apoptosis. Conclusions We identified MAFF and MAFG as novel key TFs in vascular endothelial cell apoptosis. Supplementary Information The online version contains supplementary material available at 10.1186/s12872-021-02246-5.
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Affiliation(s)
- Mangyuan Wang
- Clinical Medicine Postdoctoral Research Station, The First Affiliated Hospital of Xinjiang Medical University, 137, Liyushan Road, Xin Shi District, Urumqi, 830054, People's Republic of China.,Department of Cardiac Surgery, The First Affiliated Hospital of Xinjiang Medical University, 137, Liyushan Road, Xin Shi District, Urumqi, 830054, People's Republic of China.,Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, People's Republic of China
| | - Fen Liu
- Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, People's Republic of China
| | - Binbin Fang
- Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, People's Republic of China
| | - Qiang Huo
- Department of Cardiac Surgery, The First Affiliated Hospital of Xinjiang Medical University, 137, Liyushan Road, Xin Shi District, Urumqi, 830054, People's Republic of China.
| | - Yining Yang
- Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, 137, Liyushan Road, Xin Shi District, Urumqi, 830054, People's Republic of China. .,Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, People's Republic of China.
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15
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Zheng S, Huang H, Li Y, Wang Y, Zheng Y, Liang J, Zhang S, Liu M, Fang Z. Yin-xing-tong-mai decoction attenuates atherosclerosis via activating PPARγ-LXRα-ABCA1/ABCG1 pathway. Pharmacol Res 2021; 169:105639. [PMID: 33932607 DOI: 10.1016/j.phrs.2021.105639] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/30/2021] [Accepted: 04/20/2021] [Indexed: 12/23/2022]
Abstract
Atherosclerosis is now the major cause of mortality and morbidity worldwide. Formation of macrophage-derived foam cells is a hallmark of atherosclerosis, which is regulated by cholesterol uptake, intracellular metabolism, and efflux. PPARγ-LXRα-ABCA1/ABCG1 pathway plays an important part in regulating cholesterol efflux and this pathway could be a promising target for treating atherosclerosis. However, due to undesirable systemic effects, PPARγ agonist therapy for atherosclerosis remains challenging. Many traditional Chinese medicine has been well accepted and applied in atherosclerosis treatment. Yin-xing-tong-mai decoction (YXTMD) has been applied for treating atherosclerosis for decades. However, the mechanism remains to be explored. Here, we showed that YXTMD effectively attenuated atherosclerosis in ApoE-/- mice. YXTMD increased cholesterol efflux of foam cell by upregulation of ABCA1 and ABCG1 in vivo and in vitro. Through bioinformatic analysis and experimental validation, we found that PPARγ was an important downstream effector of YXTMD in macrophages. Reduction of PPARγ significantly decreased LXRα, ABCA1, and ABCG1 expression in macrophages, with reduced cholesterol efflux. In conclusion, these findings confirmed that YXTMD attenuated atherosclerosis by activating the PPARγ-LXRα- ABCA1/ABCG1 pathway to enhance cholesterol efflux.
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Affiliation(s)
- Shasha Zheng
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Hong Huang
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yizhuo Li
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ye Wang
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yawei Zheng
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Junya Liang
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Siqi Zhang
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ming Liu
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
| | - Zhuyuan Fang
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
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16
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Cai D, Liu H, Wang J, Hou Y, Pang T, Lin H, He C. Balasubramide derivative 3C attenuates atherosclerosis in apolipoprotein E-deficient mice: role of AMPK-STAT1-STING signaling pathway. Aging (Albany NY) 2021; 13:12160-12178. [PMID: 33901014 PMCID: PMC8109080 DOI: 10.18632/aging.202929] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 11/30/2020] [Indexed: 12/12/2022]
Abstract
We previously reported the neuroprotective effects of (+)-balasubramide derived compound 3C, but its action on atherosclerosis in vivo remains unknown. The study was designed to investigate the potential effects of 3C on atherogenesis and explore the possible underlying mechanisms. 3C ameliorated high-fat diet-induced body weight gain, hyperlipidemia, and atherosclerotic plaque burden in apolipoprotein E-deficient (ApoE-/-) mice after 10 weeks of treatment. 3C suppressed the expression of genes involved in triglyceride synthesis in liver. 3C prevented aortic inflammation as evidenced by reduction of adhesive molecule levels and macrophage infiltration. Mechanistic studies revealed that activation of AMP-activated protein kinase (AMPK) is central to the athero-protective effects of 3C. Increased AMPK activity by 3C resulted in suppressing interferon-γ (IFN-γ) induced activation of signal transducer and activator of transcription-1 (STAT1) and stimulator of interferon genes (STING) signaling pathways and downstream pro-inflammatory markers. Moreover, 3C inhibited ox-LDL triggered lipid accumulation and IFN-γ induced phenotypic switch toward M1 macrophage in RAW 264.7 cells. Our present data suggest that 3C prevents atherosclerosis via pleiotropic effects, including amelioration of lipid profiles, vascular inflammation and macrophage pro-inflammatory phenotype. 3C has the potential to be developed as a promising drug for atherosclerosis and related cardiovascular disease.
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Affiliation(s)
- Dongcheng Cai
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, Jiangsu, China
| | - Hongxia Liu
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, Jiangsu, China
| | - Jing Wang
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, Jiangsu, China
| | - Yuanlong Hou
- Jiangsu Province Key Laboratory of Drug Metabolism, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China
| | - Tao Pang
- Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Hansen Lin
- College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Chaoyong He
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, Jiangsu, China
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17
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Romeo MA, Gilardini Montani MS, Benedetti R, Giambelli L, D'Aprile R, Gaeta A, Faggioni A, Cirone M. The cross-talk between STAT1/STAT3 and ROS up-regulates PD-L1 and promotes the release of pro-inflammatory/immune suppressive cytokines in primary monocytes infected by HHV-6B. Virus Res 2020; 292:198231. [PMID: 33207265 DOI: 10.1016/j.virusres.2020.198231] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 11/10/2020] [Accepted: 11/11/2020] [Indexed: 01/22/2023]
Abstract
Programmed death ligand 1 (PD-L1) up-regulation on antigen presenting cells induces T cell dysfunction, strongly impairing immune response. Human Herpesviruses (HHV) 6B is a β-herpesvirus that, although displays a higher tropism for T cells, can infect other immune cells including monocytes and dendritic cells (DCs) and neuronal cells. We have previously shown that HHV-6B infection of primary monocytes reduced autophagy and induced Endoplasmic Reticulum (ER) stress/ Unfolded Protein Response (UPR), impairing their survival and differentiation into DCs. In this study, we found that PD-L1 expression was up-regulated by HHV-6B on the surface of infected monocytes and that its extracellular release also increased, effects known to lead to an impairment of anti-viral immune response. At molecular level, PD-L1 up-regulation correlated with the activation of a positive regulatory circuit between the increase of intracellular ROS and the activation of STAT1 and STAT3 induced by HHV-6B, accompanied by a high release of pro-inflammatory/immune suppressive cytokines. In conclusion, this study unveils new strategies put in place by HHV-6B to induce immune dysfunction and the underlying molecular pathways that could be targeted to counteract such immune suppressive effects.
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Affiliation(s)
- Maria Anele Romeo
- Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy; Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161, Rome, Italy
| | - Maria Saveria Gilardini Montani
- Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy; Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161, Rome, Italy
| | - Rossella Benedetti
- Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy; Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161, Rome, Italy
| | - Luca Giambelli
- UOC Immunohematology and Transfusional Medicine, Policlinico Umberto I, Rome, Italy
| | | | - Aurelia Gaeta
- Department of Molecular Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - Alberto Faggioni
- Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy; Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161, Rome, Italy
| | - Mara Cirone
- Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy; Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161, Rome, Italy.
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18
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Galle-Treger L, Moreau M, Ballaire R, Poupel L, Huby T, Sasso E, Troise F, Poti F, Lesnik P, Le Goff W, Gautier EL, Huby T. Targeted invalidation of SR-B1 in macrophages reduces macrophage apoptosis and accelerates atherosclerosis. Cardiovasc Res 2020; 116:554-565. [PMID: 31119270 DOI: 10.1093/cvr/cvz138] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 01/30/2019] [Accepted: 05/16/2019] [Indexed: 12/15/2022] Open
Abstract
AIMS SR-B1 is a cholesterol transporter that exerts anti-atherogenic properties in liver and peripheral tissues in mice. Bone marrow (BM) transfer studies suggested an atheroprotective role in cells of haematopoietic origin. Here, we addressed the specific contribution of SR-B1 in the monocyte/macrophage. METHODS AND RESULTS We generated mice deficient for SR-B1 in monocytes/macrophages (Lysm-Cre × SR-B1f/f) and transplanted their BM into Ldlr-/- mice. Fed a cholesterol-rich diet, these mice displayed accelerated aortic atherosclerosis characterized by larger macrophage-rich areas and decreased macrophage apoptosis compared with SR-B1f/f transplanted controls. These findings were reproduced in BM transfer studies using another atherogenic mouse recipient (SR-B1 KOliver × Cholesteryl Ester Transfer Protein). Haematopoietic reconstitution with SR-B1-/- BM conducted in parallel generated similar results to those obtained with Lysm-Cre × SR-B1f/f BM; thus suggesting that among haematopoietic-derived cells, SR-B1 exerts its atheroprotective role primarily in monocytes/macrophages. Consistent with our in vivo data, free cholesterol (FC)-induced apoptosis of macrophages was diminished in the absence of SR-B1. This effect could not be attributed to differential cellular cholesterol loading. However, we observed that expression of apoptosis inhibitor of macrophage (AIM) was induced in SR-B1-deficient macrophages, and notably upon FC-loading. Furthermore, we demonstrated that macrophages were protected from FC-induced apoptosis by AIM. Finally, AIM protein was found more present within the macrophage-rich area of the atherosclerotic lesions of SR-B1-deficient macrophages than controls. CONCLUSION Our findings suggest that macrophage SR-B1 plays a role in plaque growth by controlling macrophage apoptosis in an AIM-dependent manner.
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Affiliation(s)
| | - Martine Moreau
- Sorbonne Université, INSERM, UMR_S 1166 ICAN, F-75013, Paris, France
| | | | - Lucie Poupel
- Sorbonne Université, INSERM, UMR_S 1166 ICAN, F-75013, Paris, France
| | - Thomas Huby
- Sorbonne Université, INSERM, UMR_S 1166 ICAN, F-75013, Paris, France
| | - Emanuele Sasso
- Ceinge Biotecnologie Avanzate S.C.R.L, Via Gaetano Salvatore 486, 80145, Napoli, Italy.,Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, 80131, Napoli, Italy
| | - Fulvia Troise
- Ceinge Biotecnologie Avanzate S.C.R.L, Via Gaetano Salvatore 486, 80145, Napoli, Italy
| | - Francesco Poti
- Department of Medicine and Surgery, Unit of Neurosciences, University of Parma, Parma, Italy
| | - Philippe Lesnik
- Sorbonne Université, INSERM, UMR_S 1166 ICAN, F-75013, Paris, France
| | - Wilfried Le Goff
- Sorbonne Université, INSERM, UMR_S 1166 ICAN, F-75013, Paris, France
| | | | - Thierry Huby
- Sorbonne Université, INSERM, UMR_S 1166 ICAN, F-75013, Paris, France
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Diospyrin Modulates Inflammation in Poly I:C-Induced Macrophages via ER Stress-Induced Calcium-CHOP Pathway. Processes (Basel) 2020. [DOI: 10.3390/pr8091050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Diospyrin, plant-derived bisnaphthoquinonoid, is known to have anticancer activity. However, pharmacological activity of diospyrin on viral infection is not well known. We investigated effects of diospyrin on macrophages induced by polyinosinic-polycytidylic acid (poly I:C), a mimic of double-stranded viral RNA. Various cytokines, intracellular calcium, nitric oxide (NO), phosphorylated p38 MAPK, and phosphorylated ERK1/2 as well as mRNA expressions of transcription factors were evaluated. Diospyrin significantly reduced NO production, granulocyte-macrophage colony-stimulating factor production, and intracellular calcium release in poly I:C-induced RAW 264.7. The phosphorylation of p38 MAPK and ERK1/2 was also significantly suppressed. Additionally, diospyrin inhibited mRNA levels of nitric oxide synthase 2, C/EBP homologous protein (CHOP), calcium/calmodulin dependent protein kinase II alpha, signal transducers and activators of transcription 1 (STAT1), STAT3, STAT4, Janus kinase 2, first apoptosis signal receptor, c-Jun, and c-Fos in poly I:C-induced RAW 264.7. Taken together, this study represents that diospyrin might have the inhibitory activity against viral inflammation such as excessive production of inflammatory mediators in poly I:C-induced RAW 264.7 via ER stress-induced calcium-CHOP pathway.
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20
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La Manna S, Lopez-Sanz L, Bernal S, Jimenez-Castilla L, Prieto I, Morelli G, Gomez-Guerrero C, Marasco D. Antioxidant Effects of PS5, a Peptidomimetic of Suppressor of Cytokine Signaling 1, in Experimental Atherosclerosis. Antioxidants (Basel) 2020; 9:antiox9080754. [PMID: 32824091 PMCID: PMC7465353 DOI: 10.3390/antiox9080754] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/07/2020] [Accepted: 08/10/2020] [Indexed: 12/13/2022] Open
Abstract
The chronic activation of the Janus kinase/signal transducer and activator of the transcription (JAK/STAT) pathway is linked to oxidative stress, inflammation and cell proliferation. Suppressors of cytokine signaling (SOCS) proteins negatively regulate the JAK/STAT, and SOCS1 possesses a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Several studies showed that KIR-SOCS1 mimetics can be considered valuable therapeutics in several disorders (e.g., diabetes, neurological disorders and atherosclerosis). Herein, we investigated the antioxidant and atheroprotective effects of PS5, a peptidomimetic of KIR-SOCS1, both in vitro (vascular smooth muscle cells and macrophages) and in vivo (atherosclerosis mouse model) by analyzing gene expression, intracellular O2•− production and atheroma plaque progression and composition. PS5 was revealed to be able to attenuate NADPH oxidase (NOX1 and NOX4) and pro-inflammatory gene expression, to upregulate antioxidant genes and to reduce atheroma plaque size, lipid content and monocyte/macrophage accumulation. These findings confirm that KIR-SOCS1-based drugs could be excellent antioxidant agents to contrast atherosclerosis.
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Affiliation(s)
- Sara La Manna
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples “Federico II”, 80134 Naples, Italy; (S.L.M.); (G.M.)
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain; (L.L.-S.); (S.B.); (L.J.-C.); (I.P.)
| | - Laura Lopez-Sanz
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain; (L.L.-S.); (S.B.); (L.J.-C.); (I.P.)
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
| | - Susana Bernal
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain; (L.L.-S.); (S.B.); (L.J.-C.); (I.P.)
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
| | - Luna Jimenez-Castilla
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain; (L.L.-S.); (S.B.); (L.J.-C.); (I.P.)
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
| | - Ignacio Prieto
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain; (L.L.-S.); (S.B.); (L.J.-C.); (I.P.)
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
| | - Giancarlo Morelli
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples “Federico II”, 80134 Naples, Italy; (S.L.M.); (G.M.)
| | - Carmen Gomez-Guerrero
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
- Correspondence: (C.G.-G.); (D.M.)
| | - Daniela Marasco
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples “Federico II”, 80134 Naples, Italy; (S.L.M.); (G.M.)
- Correspondence: (C.G.-G.); (D.M.)
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21
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Sun L, Zhang W, Zhao Y, Wang F, Liu S, Liu L, Zhao L, Lu W, Li M, Xu Y. Dendritic Cells and T Cells, Partners in Atherogenesis and the Translating Road Ahead. Front Immunol 2020; 11:1456. [PMID: 32849502 PMCID: PMC7403484 DOI: 10.3389/fimmu.2020.01456] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 06/04/2020] [Indexed: 12/13/2022] Open
Abstract
Atherosclerosis is a chronic process associated with arterial inflammation, the accumulation of lipids, plaque formation in vessel walls, and thrombosis with late mortal complications such as myocardial infarction and ischemic stroke. Immune and inflammatory responses have significant effects on every phase of atherosclerosis. Increasing evidence has shown that both innate and adaptive “arms” of the immune system play important roles in regulating the progression of atherosclerosis. Accumulating evidence suggests that a unique type of innate immune cell, termed dendritic cells (DCs), play an important role as central instigators, whereas adaptive immune cells, called T lymphocytes, are crucial as active executors of the DC immunity in atherogenesis. These two important immune cell types work in pairs to establish pro-atherogenic or atheroprotective immune responses in vascular tissues. Therefore, understanding the role of DCs and T cells in atherosclerosis is extremely important. Here, in this review, we will present a complete overview, based on existing knowledge of these two cell types in the atherosclerotic microenvironment, and discuss some of the novel means of targeting DCs and T cells as therapeutic tactics for the treatment of atherosclerosis.
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Affiliation(s)
- Li Sun
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Wenjie Zhang
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Yanfang Zhao
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Fengge Wang
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Shan Liu
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Lei Liu
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Lin Zhao
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Wei Lu
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Minghui Li
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Yuekang Xu
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
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Zhu L, Wang F, Yang H, Zhang J, Chen S. Low shear stress damages endothelial function through STAT1 in endothelial cells (ECs). J Physiol Biochem 2020; 76:147-157. [PMID: 32037480 DOI: 10.1007/s13105-020-00729-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 01/21/2020] [Indexed: 01/04/2023]
Abstract
Low shear stress (LSS) occurs in areas where atherosclerosis is prevalent. Many studies have revealed that signal transducer and activator of transcription 1 (STAT1) plays a significant role in cardiovascular disease. Nonetheless, the mechanism underlying the connection between STAT1 and LSS is not fully understood. The purpose of this study was to investigate the link between LSS and STAT1 in endothelial cells (ECs). Monolayer endothelial cells were stimulated or not stimulated by LSS. Protein expression and phosphorylation levels were determined by western blotting. Immunofluorescence was used to compare the protein expression differences in bifurcated and non-bifurcated human coronary arteries. Endothelial function was assessed by using a dihydroethidium assay, real-time PCR, western blotting and nitric oxide (NO)-sensitive fluorophore. Results showed that STAT1 played a key role in LSS-induced endothelium damage. Firstly, LSS activated STAT1, as evidenced by LSS-induced STAT1 (Tyr701) phosphorylation in ECs in vitro and the increased intimal STAT1 expression at bifurcation of human coronary arteries. Secondly, LSS-induced STAT1 phosphorylation was positively regulated by inhibitor of nuclear factor kappa-B kinase ε (IKKε). Additionally, LSS-promoted inflammatory factor expression was markedly reversed by silencing STAT1 (siSTAT1). LSS also increased reactive oxygen species (ROS) level and decreased endogenous NO release: however, siSTAT1 reversed these adverse effects through upregulating the antioxidant gene heme oxygenase-1(HO-1) and downregulating endothelial nitric oxide synthase (eNOS) Thr495 phosphorylation. According to our results, LSS-mediated EC injury may be associated with the activation of STAT1. Strategies designed to reduce STAT1 expression or inhibit STAT1 activation may be effective approaches for reducing the incidence of atherosclerosis.
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Affiliation(s)
- Linlin Zhu
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Feng Wang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Hongfeng Yang
- Department of intensive Care Unit, Affiliated People' Hospital of Jiangsu University, Zhenjiang, China
| | - Junjie Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
| | - Shaoliang Chen
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
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Loss of PARP-1 attenuates diabetic arteriosclerotic calcification via Stat1/Runx2 axis. Cell Death Dis 2020; 11:22. [PMID: 31924749 PMCID: PMC6954221 DOI: 10.1038/s41419-019-2215-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 07/03/2019] [Accepted: 10/25/2019] [Indexed: 12/18/2022]
Abstract
Accelerated atherosclerotic calcification is responsible for plaque burden, especially in diabetes. The regulatory mechanism for atherosclerotic calcification in diabetes is poorly characterized. Here we show that deletion of PARP-1, a main enzyme in diverse metabolic complications, attenuates diabetic atherosclerotic calcification and decreases vessel stiffening in mice through Runx2 suppression. Specifically, PARP-1 deficiency reduces diabetic arteriosclerotic calcification by regulating Stat1-mediated synthetic phenotype switching of vascular smooth muscle cells and macrophage polarization. Meanwhile, both vascular smooth muscle cells and macrophages manifested osteogenic differentiation in osteogenic media, which was attenuated by PARP-1/Stat1 inhibition. Notably, Stat1 acts as a positive transcription factor by directly binding to the promoter of Runx2 and promoting atherosclerotic calcification in diabetes. Our results identify a new function of PARP-1, in which metabolism disturbance-related stimuli activate the Runx2 expression mediated by Stat1 transcription to facilitate diabetic arteriosclerotic calcification. PARP-1 inhibition may therefore represent a useful therapy for this challenging complication.
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Herrero-Fernandez B, Gomez-Bris R, Somovilla-Crespo B, Gonzalez-Granado JM. Immunobiology of Atherosclerosis: A Complex Net of Interactions. Int J Mol Sci 2019; 20:E5293. [PMID: 31653058 PMCID: PMC6862594 DOI: 10.3390/ijms20215293] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 10/21/2019] [Accepted: 10/22/2019] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease is the leading cause of mortality worldwide, and atherosclerosis the principal factor underlying cardiovascular events. Atherosclerosis is a chronic inflammatory disease characterized by endothelial dysfunction, intimal lipid deposition, smooth muscle cell proliferation, cell apoptosis and necrosis, and local and systemic inflammation, involving key contributions to from innate and adaptive immunity. The balance between proatherogenic inflammatory and atheroprotective anti-inflammatory responses is modulated by a complex network of interactions among vascular components and immune cells, including monocytes, macrophages, dendritic cells, and T, B, and foam cells; these interactions modulate the further progression and stability of the atherosclerotic lesion. In this review, we take a global perspective on existing knowledge about the pathogenesis of immune responses in the atherosclerotic microenvironment and the interplay between the major innate and adaptive immune factors in atherosclerosis. Studies such as this are the basis for the development of new therapies against atherosclerosis.
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Affiliation(s)
- Beatriz Herrero-Fernandez
- LamImSys Lab. Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain.
- Departamento de Fisiología. Facultad de Medicina. Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain.
| | - Raquel Gomez-Bris
- LamImSys Lab. Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain.
| | | | - Jose Maria Gonzalez-Granado
- LamImSys Lab. Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain.
- Departamento de Fisiología. Facultad de Medicina. Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain.
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.
- CIBER de Enfermedades Cardiovasculares, 28029 Madrid, Spain.
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25
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Hao D, Danbin W, Maojuan G, Chun S, Bin L, Lin Y, Yingxin S, Guanwei F, Yefei C, Qing G, Xijuan J. Ethanol extracts of Danlou tablet attenuate atherosclerosis via inhibiting inflammation and promoting lipid effluent. Pharmacol Res 2019; 146:104306. [DOI: 10.1016/j.phrs.2019.104306] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 06/03/2019] [Accepted: 06/06/2019] [Indexed: 12/25/2022]
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26
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Lopes-Virella MF, Virella G. Modified LDL Immune Complexes and Cardiovascular Disease. Curr Med Chem 2019; 26:1680-1692. [DOI: 10.2174/0929867325666180524114429] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 11/17/2017] [Accepted: 12/28/2017] [Indexed: 12/17/2022]
Abstract
Modified forms of LDL, both spontaneously formed in the organism or prepared in the laboratory, are immunogenic. As a consequence, antigen-antibody complexes (immune complexes, IC) formed in vivo can be measured in the peripheral blood, and their levels are strong predictors of cardiovascular disease (CVD). It has been possible to generate antibodies that recognize different LDL modifications, allowing the analysis of circulating IC constitution. Clinical studies showed that the antigenic constitution of the IC has a modulating effect on the development of CVD. Patients whose IC react strongly with antibodies to copper oxidized LDL (oxLDL) show progressive development of atherosclerosis as demonstrated by increased intima–media thickness and increased coronary calcification scores. In contrast, patients whose IC react strongly with antibodies to the heavily oxidized malondialdehyde LDL prepared in vitro (MDA-LDL) are at a high risk of acute vascular events, mainly myocardial infarction. In vitro studies have shown that while oxLDL IC induce both cell proliferation and mild to moderate macrophage apoptosis, MDA-LDL IC induce a more marked macrophage apoptosis but not cell proliferation. In addition, MDA-LDL IC induce the release of higher levels of matrix metalloproteinases and TNF than oxLDL IC. High levels of TNF are likely to be a major factor leading to apoptosis and high levels of metalloproteinases are likely to play a role in the thinning of the fibrous cap of the atheromatous plaque. The combination of apoptosis and fibrous cap thinning is a well-known characteristic of vulnerable plaques, which are more prone to rupture and responsible for the majority of acute cardiovascular events.
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Affiliation(s)
- Maria F. Lopes-Virella
- Department of Medicine, Medical University of South Carolina, Charleston, SC, USA; Ralph A. Johnson VA Medical Center, Charleston, SC, United States
| | - Gabriel Virella
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
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27
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Shao X, Wang B, Mu K, Li L, Li Q, He W, Yao Q, Jia X, Zhang JA. Key gene co-expression modules and functional pathways involved in the pathogenesis of Graves' disease. Mol Cell Endocrinol 2018; 474:252-259. [PMID: 29614339 DOI: 10.1016/j.mce.2018.03.015] [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: 11/21/2017] [Revised: 03/27/2018] [Accepted: 03/28/2018] [Indexed: 12/13/2022]
Abstract
Graves' disease (GD) is a common autoimmune thyroid disease characterized by positive thyroid stimulating hormone receptor antibody. To better understand its molecular pathogenesis, we adopted the weighted gene co-expression network analysis to reveal co-expression modules of key genes involved in the pathogenesis of GD, protein-protein interaction network analysis to identify the hub genes related to GD development and functional analyses to explore their possible functions. Our results showed that 1) a total of 2667 differentially expressed genes in our microarray study and 16 different gene co-expression modules were associated with GD, and 2) the most significant module was associated with the percentage of macrophages, T follicular helper cells and CD4+ memory T cells and mainly enriched in immune regulation and immune response. Overall, our study reveals several key gene co-expression modules and functional pathways involved in GD, which provides some novel insights into the pathogenesis of GD.
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Affiliation(s)
- Xiaoqing Shao
- Department of Endocrinology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Bin Wang
- Department of Endocrinology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Kaida Mu
- Department of Endocrinology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Ling Li
- Department of Endocrinology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Qian Li
- Department of Endocrinology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Weiwei He
- Department of Endocrinology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Qiuming Yao
- Department of Endocrinology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Xi Jia
- Department of Endocrinology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Jin-An Zhang
- Department of Endocrinology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China.
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28
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Abstract
The endoplasmic reticulum (ER) is critical in protein processing and particularly in ensuring that proteins undergo their correct folding to exert their functionality. What is becoming increasingly clear is that the ER may undergo increasing stress brought about by nutrient deprivation, hypoxia, oxidized lipids, point mutations in secreted proteins, cellular differentiation or significant deviation from metabolic set points, and loss of Ca2+ homeostasis, with detrimental effects on ER-resident calcium-dependent chaperones, alone or in combination. This results in the unfolded protein response (UPR) that is a repair mechanism to limit the formation of newly damaged proteins until ER homeostasis is restored, though may result in increased cell death. ER stress has been shown to be implicated in a variety of diseases. Statins are well-known cholesterol-lowering drugs and have been extensively reported to possess beneficial cholesterol-independent effects in a variety of human diseases. This review focuses on the concept of ER stress, the underlying molecular mechanisms and their relationship to the pathophysiology and, finally, the role of statins in moderating ER stress and UPR.
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Reardon CA, Lingaraju A, Schoenfelt KQ, Zhou G, Cui C, Jacobs-El H, Babenko I, Hoofnagle A, Czyz D, Shuman H, Vaisar T, Becker L. Obesity and Insulin Resistance Promote Atherosclerosis through an IFNγ-Regulated Macrophage Protein Network. Cell Rep 2018; 23:3021-3030. [PMID: 29874587 PMCID: PMC6082182 DOI: 10.1016/j.celrep.2018.05.010] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 03/01/2018] [Accepted: 05/02/2018] [Indexed: 01/02/2023] Open
Abstract
Type 2 diabetes (T2D) is associated with increased risk for atherosclerosis; however, the mechanisms underlying this relationship are poorly understood. Macrophages, which are activated in T2D and causatively linked to atherogenesis, are an attractive mechanistic link. Here, we use proteomics to show that diet-induced obesity and insulin resistance (obesity/IR) modulate a pro-atherogenic "macrophage-sterol-responsive-network" (MSRN), which, in turn, predisposes macrophages to cholesterol accumulation. We identify IFNγ as the mediator of obesity/IR-induced MSRN dysregulation and increased macrophage cholesterol accumulation and show that obesity/IR primes T cells to increase IFNγ production. Accordingly, myeloid cell-specific deletion of the IFNγ receptor (Ifngr1-/-) restores MSRN proteins, attenuates macrophage cholesterol accumulation and atherogenesis, and uncouples the strong relationship between hyperinsulinemia and aortic root lesion size in hypercholesterolemic Ldlr-/- mice with obesity/IR, but does not affect these parameters in Ldlr-/- mice without obesity/IR. Collectively, our findings identify an IFNγ-macrophage pathway as a mechanistic link between obesity/IR and accelerated atherogenesis.
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Affiliation(s)
- Catherine A Reardon
- Committee on Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL 60637, USA; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA
| | - Amulya Lingaraju
- Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA; Committee on Molecular Pathogenesis and Molecular Medicine, The University of Chicago, Chicago, IL 60637, USA
| | - Kelly Q Schoenfelt
- Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA
| | - Guolin Zhou
- Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA
| | - Chang Cui
- Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA
| | - Hannah Jacobs-El
- Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA
| | - Ilona Babenko
- Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Andrew Hoofnagle
- Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA
| | - Daniel Czyz
- Department of Microbiology, The University of Chicago, Chicago, IL 60637, USA
| | - Howard Shuman
- Department of Microbiology, The University of Chicago, Chicago, IL 60637, USA; Committe on Microbiology, The University of Chicago, Chicago, IL 60637, USA
| | - Tomas Vaisar
- Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Lev Becker
- Committee on Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL 60637, USA; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
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30
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Targeted inhibition of STATs and IRFs as a potential treatment strategy in cardiovascular disease. Oncotarget 2018; 7:48788-48812. [PMID: 27166190 PMCID: PMC5217051 DOI: 10.18632/oncotarget.9195] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 04/22/2016] [Indexed: 02/06/2023] Open
Abstract
Key factors contributing to early stages of atherosclerosis and plaque development include the pro-inflammatory cytokines Interferon (IFN)α, IFNγ and Interleukin (IL)-6 and Toll-like receptor 4 (TLR4) stimuli. Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT) and Interferon Regulatory Factor (IRF) families. In particular, STAT1, 2 and 3; IRF1 and 8 have recently been recognized as prominent modulators of inflammation, especially in immune and vascular cells during atherosclerosis. Moreover, inflammation-mediated activation of these STATs and IRFs coordinates a platform for synergistic amplification leading to pro-atherogenic responses. Searches for STAT3-targeting compounds, exploring the pTyr-SH2 interaction area of STAT3, yielded many small molecules including natural products. Only a few inhibitors for other STATs, but none for IRFs, are described. Promising results for several STAT3 inhibitors in recent clinical trials predicts STAT3-inhibiting strategies may find their way to the clinic. However, many of these inhibitors do not seem STAT-specific, display toxicity and are not very potent. This illustrates the need for better models, and screening and validation tools for novel STAT and IRF inhibitors. This review presents a summary of these findings. It postulates STAT1, STAT2 and STAT3 and IRF1 and IRF8 as interesting therapeutic targets and targeted inhibition could be a potential treatment strategy in CVDs. In addition, it proposes a pipeline approach that combines comparative in silico docking of STAT-SH2 and IRF-DBD models with in vitro STAT and IRF activation inhibition validation, as a novel tool to screen multi-million compound libraries and identify specific inhibitors for STATs and IRFs.
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31
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Keeley TP, Siow RCM, Jacob R, Mann GE. Reduced SERCA activity underlies dysregulation of Ca 2+ homeostasis under atmospheric O 2 levels. FASEB J 2017; 32:2531-2538. [PMID: 29273673 PMCID: PMC5901376 DOI: 10.1096/fj.201700685rrr] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Unregulated increases in cellular Ca2+ homeostasis are a hallmark of pathophysiological conditions and a key trigger of cell death. Endothelial cells cultured under physiologic O2 conditions (5% O2) exhibit a reduced cytosolic Ca2+ response to stimulation. The mechanism for reduced plateau [Ca2+]i upon stimulation was due to increased sarco/endoplasmic reticulum Ca2+ ATPase (SERCA)-mediated reuptake rather than changes in Ca2+ influx capacity. Agonist-stimulated phosphorylation of the SERCA regulatory protein phospholamban was increased in cells cultured under 5% O2. Elevation of cytosolic and mitochondrial [Ca2+] and cell death after prolonged ionomycin treatment, as a model of Ca2+ overload, were lower when cells were cultured long-term under 5% compared with 18% O2. This protection was abolished by cotreatment with the SERCA inhibitor cyclopiazonic acid. Taken together, these results demonstrate that culturing cells under hyperoxic conditions reduces their ability to efficiently regulate [Ca2+]i, resulting in greater sensitivity to cytotoxic stimuli.-Keeley, T. P., Siow, R. C. M., Jacob, R., Mann, G. E. Reduced SERCA activity underlies dysregulation of Ca2+ homeostasis under atmospheric O2 levels.
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Affiliation(s)
- Thomas P Keeley
- King's British Heart Foundation Centre for Research Excellence, School of Cardiovascular Medicine and Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Richard C M Siow
- King's British Heart Foundation Centre for Research Excellence, School of Cardiovascular Medicine and Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Ron Jacob
- King's British Heart Foundation Centre for Research Excellence, School of Cardiovascular Medicine and Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Giovanni E Mann
- King's British Heart Foundation Centre for Research Excellence, School of Cardiovascular Medicine and Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
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32
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Cathelicidin-WA polarizes E. coli K88-induced M1 macrophage to M2-like macrophage in RAW264.7 cells. Int Immunopharmacol 2017; 54:52-59. [PMID: 29101873 DOI: 10.1016/j.intimp.2017.10.013] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 09/24/2017] [Accepted: 10/11/2017] [Indexed: 12/19/2022]
Abstract
Immune cells - macrophages induced by E. coli K88 will lead to a pro-inflammatory response, which is important in host defense. Cathelicidin-WA (CWA) is an efficient antimicrobial peptide (AMP) and can exert immunomodulatory properties. Many studies have demonstrated that AMP can modulate cellular subsets but whether CWA can regulate macrophage polarization by transferring E. coli K88-induced M1 macrophage towards M2 one that of anti-inflammation remains unclear. In this study, E. coli K88 increased the expression of pro-inflammatory cytokines interleukin-6, interleukin-1β, tumor necrosis factor-α and chemokine CCL3 in RAW264.7 cells with a time-dependent manner, as well as the expression of reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS). On this basis, CWA significantly decreased the pro-inflammatory molecules but increased the anti-inflammatory mediators interleukin-4, interleukin-10 and other M2-related genes in E. coli K88-induced macrophages. Western blot analysis indicated that CWA suppressed the expression of TLR-4 and the phosphorylation of STAT1 and NF-κB which modulated M1 macrophage while induced the phosphorylation of STAT6 which activated M2 macrophage. Double staining of M1-specific CD86 and M2-specific CD206 also proved the hypothesis. These results suggested that CWA might dampen the inflammation by modulating M1 phenotype to M2 phenotype in E. coli K88-induced macrophages.
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33
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Mehta NN, Teague HL, Swindell WR, Baumer Y, Ward NL, Xing X, Baugous B, Johnston A, Joshi AA, Silverman J, Barnes DH, Wolterink L, Nair RP, Stuart PE, Playford M, Voorhees JJ, Sarkar MK, Elder JT, Gallagher K, Ganesh SK, Gudjonsson JE. IFN-γ and TNF-α synergism may provide a link between psoriasis and inflammatory atherogenesis. Sci Rep 2017; 7:13831. [PMID: 29062018 PMCID: PMC5653789 DOI: 10.1038/s41598-017-14365-1] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 10/10/2017] [Indexed: 12/14/2022] Open
Abstract
Chronic inflammation is a critical component of atherogenesis, however, reliable human translational models aimed at characterizing these mechanisms are lacking. Psoriasis, a chronic inflammatory skin disease associated with increased susceptibility to atherosclerosis, provides a clinical human model that can be utilized to investigate the links between chronic inflammation and atherosclerosis development. We sought to investigate key biological processes in psoriasis skin and human vascular tissue to identify biological components that may promote atherosclerosis in chronic inflammatory conditions. Using a bioinformatics approach of human skin and vascular tissue, we determined IFN-γ and TNF-α are the dominant pro-inflammatory signals linking atherosclerosis and psoriasis. We then stimulated primary aortic endothelial cells and ex-vivo atherosclerotic tissue with IFN-γ and TNF-α and found they synergistically increased monocyte and T-cell chemoattractants, expression of adhesion molecules on the endothelial cell surface, and decreased endothelial barrier integrity in vitro, therefore increasing permeability. Our data provide strong evidence of synergism between IFN-γ and TNF- α in inflammatory atherogenesis and provide rationale for dual cytokine antagonism in future studies.
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Affiliation(s)
- Nehal N Mehta
- National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Heather L Teague
- National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | | | - Yvonne Baumer
- National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Nicole L Ward
- Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA
| | - Xianying Xing
- Department of Dermatology, Univ. of Michigan, Ann Arbor, MI, USA
| | - Brooke Baugous
- Department of Dermatology, Univ. of Michigan, Ann Arbor, MI, USA
| | - Andrew Johnston
- Department of Dermatology, Univ. of Michigan, Ann Arbor, MI, USA
| | - Aditya A Joshi
- National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Joanna Silverman
- National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Drew H Barnes
- Department of Dermatology, Univ. of Michigan, Ann Arbor, MI, USA
| | - Liza Wolterink
- Department of Dermatology, Univ. of Michigan, Ann Arbor, MI, USA
| | - Rajan P Nair
- Department of Dermatology, Univ. of Michigan, Ann Arbor, MI, USA
| | - Philip E Stuart
- Department of Dermatology, Univ. of Michigan, Ann Arbor, MI, USA
| | - Martin Playford
- National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - John J Voorhees
- Department of Dermatology, Univ. of Michigan, Ann Arbor, MI, USA
| | - Mrinal K Sarkar
- Department of Dermatology, Univ. of Michigan, Ann Arbor, MI, USA
| | - James T Elder
- Department of Dermatology, Univ. of Michigan, Ann Arbor, MI, USA
| | - Katherine Gallagher
- Department of Surgery, Division of Vascular Surgery, Univ. of Michigan, Ann Arbor, MI, USA
| | - Santhi K Ganesh
- Department of Internal Medicine, Division of Cardiovascular Medicine, and Department of Human Genetics, Univ. of Michigan, Ann Arbor, MI, USA
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Nagenborg J, Goossens P, Biessen EAL, Donners MMPC. Heterogeneity of atherosclerotic plaque macrophage origin, phenotype and functions: Implications for treatment. Eur J Pharmacol 2017; 816:14-24. [PMID: 28989084 DOI: 10.1016/j.ejphar.2017.10.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 10/02/2017] [Accepted: 10/04/2017] [Indexed: 01/01/2023]
Abstract
Macrophages are key players in atherosclerotic lesions, regulating the local inflammatory milieu and plaque stability by the secretion of many inflammatory molecules, growth factors and cytokines. Monocytes have long been considered to be the main source of plaque macrophages. However, recent findings provide evidence for proliferation of local macrophages or transdifferentiation from other vascular cells as alternative sources. Recent years of research focused on the further identification and characterisation of macrophage phenotypes and functions. In this review we describe the advances in our understanding of monocyte and macrophage heterogeneity and its implications for specific therapeutic interventions, aiming to reduce the ever growing significant risk of cardiovascular events without any detrimental side effects on the patient's immune response.
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Affiliation(s)
- Jan Nagenborg
- Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands
| | - Pieter Goossens
- Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands
| | - Erik A L Biessen
- Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands
| | - Marjo M P C Donners
- Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands.
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35
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Cellular and Molecular Mechanisms of Diabetic Atherosclerosis: Herbal Medicines as a Potential Therapeutic Approach. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:9080869. [PMID: 28883907 PMCID: PMC5572632 DOI: 10.1155/2017/9080869] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 06/30/2017] [Accepted: 07/10/2017] [Indexed: 01/09/2023]
Abstract
An increasing number of patients diagnosed with diabetes mellitus eventually develop severe coronary atherosclerosis disease. Both type 1 and type 2 diabetes mellitus increase the risk of cardiovascular disease associated with atherosclerosis. The cellular and molecular mechanisms affecting the incidence of diabetic atherosclerosis are still unclear, as are appropriate strategies for the prevention and treatment of diabetic atherosclerosis. In this review, we discuss progress in the study of herbs as potential therapeutic agents for diabetic atherosclerosis.
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Chemaly ER, Troncone L, Lebeche D. SERCA control of cell death and survival. Cell Calcium 2017; 69:46-61. [PMID: 28747251 DOI: 10.1016/j.ceca.2017.07.001] [Citation(s) in RCA: 152] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 07/03/2017] [Accepted: 07/03/2017] [Indexed: 12/31/2022]
Abstract
Intracellular calcium (Ca2+) is a critical coordinator of various aspects of cellular physiology. It is increasingly apparent that changes in cellular Ca2+ dynamics contribute to the regulation of normal and pathological signal transduction that controls cell growth and survival. Aberrant perturbations in Ca2+ homeostasis have been implicated in a range of pathological conditions, such as cardiovascular diseases, diabetes, tumorigenesis and steatosis hepatitis. Intracellular Ca2+ concentrations are therefore tightly regulated by a number of Ca2+ handling enzymes, proteins, channels and transporters located in the plasma membrane and in Ca2+ storage organelles, which work in concert to fine tune a temporally and spatially precise Ca2+ signal. Chief amongst them is the sarco/endoplasmic reticulum (SR/ER) Ca2+ ATPase pump (SERCA) which actively re-accumulates released Ca2+ back into the SR/ER, therefore maintaining Ca2+ homeostasis. There are at least 14 different SERCA isoforms encoded by three ATP2A1-3 genes whose expressions are species- and tissue-specific. Altered SERCA expression and activity results in cellular malignancy and induction of ER stress and ER stress-associated apoptosis. The role of SERCA misregulation in the control of apoptosis in various cell types and disease setting with prospective therapeutic implications is the focus of this review. Ca2+ is a double edge sword for both life as well as death, and current experimental evidence supports a model in which Ca2+ homeostasis and SERCA activity represent a nodal point that controls cell survival. Pharmacological or genetic targeting of this axis constitutes an incredible therapeutic potential to treat different diseases sharing similar biological disorders.
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Affiliation(s)
- Elie R Chemaly
- Division of Nephrology and Hypertension, Department of Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Luca Troncone
- Cardiovascular Research Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Djamel Lebeche
- Cardiovascular Research Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Diabetes, Obesity and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Graduate School of Biological Sciences, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
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TWEAK blockade decreases atherosclerotic lesion size and progression through suppression of STAT1 signaling in diabetic mice. Sci Rep 2017; 7:46679. [PMID: 28447667 PMCID: PMC5406837 DOI: 10.1038/srep46679] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 03/27/2017] [Indexed: 11/30/2022] Open
Abstract
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK/Tnfsf12) is a cytokine implicated in different steps associated with vascular remodeling. However, the role of TWEAK under hyperglycemic conditions is currently unknown. Using two different approaches, genetic deletion of Tnfsf12 and treatment with a TWEAK blocking mAb, we have analyzed the effect of TWEAK inhibition on atherosclerotic plaque progression and stability in streptozotocin-induced diabetic ApoE deficient mice. Genetic inactivation of Tnfsf12 reduced atherosclerosis extension and severity in diabetic ApoE deficient mice. Tnfsf12 deficient mice display a more stable plaque phenotype characterized by lower lipid and macrophage content within atherosclerotic plaques. A similar phenotype was observed in diabetic mice treated with anti-TWEAK mAb. The proatherosclerotic effects of TWEAK were mediated, at least in part, by STAT1 activation and expression of proinflammatory target genes (CCL5, CXCL10 and ICAM-1), both in plaques of ApoE mice and in cultured vascular smooth muscle cells (VSMCs) under hyperglycemic conditions. Loss-of-function experiments demonstrated that TWEAK induces proinflammatory genes mRNA expression through its receptor Fn14 and STAT1 activation in cultured VSMCs. Overall, TWEAK blockade delay plaque progression and alter plaque composition in diabetic atherosclerotic mice. Therapies aimed to inhibit TWEAK expression and/or function could protect from diabetic vascular complications.
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Layhadi JA, Fountain SJ. Influence of ER leak on resting cytoplasmic Ca 2+ and receptor-mediated Ca 2+ signalling in human macrophage. Biochem Biophys Res Commun 2017; 487:633-639. [PMID: 28435065 DOI: 10.1016/j.bbrc.2017.04.106] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 04/19/2017] [Indexed: 01/26/2023]
Abstract
Mechanisms controlling endoplasmic reticulum (ER) Ca2+ homeostasis are important regulators of resting cytoplasmic Ca2+ concentration ([Ca2+]cyto) and receptor-mediated Ca2+ signalling. Here we investigate channels responsible for ER Ca2+ leak in THP-1 macrophage and human primary macrophage. In the absence of extracellular Ca2+ we employ ionomycin action at the plasma membrane to stimulate ER Ca2+ leak. Under these conditions ionomycin elevates [Ca2+]cyto revealing a Ca2+ leak response which is abolished by thapsigargin. IP3 receptors (Xestospongin C, 2-APB), ryanodine receptors (dantrolene), and translocon (anisomycin) inhibition facilitated ER Ca2+ leak in model macrophage, with translocon inhibition also reducing resting [Ca2+]cyto. In primary macrophage, translocon inhibition blocks Ca2+ leak but does not influence resting [Ca2+]cyto. We identify a role for translocon-mediated ER Ca2+ leak in receptor-mediated Ca2+ signalling in both model and primary human macrophage, whereby the Ca2+ response to ADP (P2Y receptor agonist) is augmented following anisomycin treatment. In conclusion, we demonstrate a role of ER Ca2+ leak via the translocon in controlling resting cytoplasmic Ca2+ in model macrophage and receptor-mediated Ca2+ signalling in model macrophage and primary macrophage.
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Affiliation(s)
- Janice A Layhadi
- School of Biological Sciences, Biomedical Research Centre, University of East Anglia, Norwich Research Park, NR4 7TJ, UK
| | - Samuel J Fountain
- School of Biological Sciences, Biomedical Research Centre, University of East Anglia, Norwich Research Park, NR4 7TJ, UK.
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Nikiforov NG, Elizova NV, Bukrinsky M, Dubrovsky L, Makeev VJ, Wakabayashi Y, Liu P, Foxx KK, Kruth HS, Jin X, Zakiev ER, Orekhov AN. Use of Primary Macrophages for Searching Novel Immunocorrectors. Curr Pharm Des 2017; 23:915-920. [PMID: 28124601 DOI: 10.2174/1381612823666170125110128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 01/11/2017] [Indexed: 11/22/2022]
Abstract
In this mini-review, the role of macrophage phenotypes in atherogenesis is considered. Recent studies on distribution of M1 and M2 macrophages in different types of atherosclerotic lesions indicate that macrophages exhibit a high degree of plasticity of phenotype in response to various conditions in microenvironment. The effect of the accumulation of cholesterol, a key event in atherogenesis, on the macrophage phenotype is also discussed. The article presents the results of transcriptome analysis of cholesterol-loaded macrophages revealing genes involved in immune response whose expression rate has changed the most. It turned out that the interaction of macrophages with modified LDL leads to higher expression levels of pro-inflammatory marker TNF-α and antiinflammatory marker CCL18. Phenotypic profile of macrophage activation could be a good target for testing of novel anti-atherogenic immunocorrectors. A number of anti-atherogenic drugs were tested as potential immunocorrectors using primary macrophage-based model.
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Affiliation(s)
- Nikita G Nikiforov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russian Federation
| | - Natalia V Elizova
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russian Federation
| | - Michael Bukrinsky
- GW School of Medicine and Health Sciences, George Washington University, 20037 Washington, DC, United States
| | - Larisa Dubrovsky
- GW School of Medicine and Health Sciences, George Washington University, 20037 Washington, DC, United States
| | - Vsevolod J Makeev
- Vavilov Institute of General Genetics, Russian Academy of Sciences, 119333 Moscow, Russian Federation
| | - Yoshiyuki Wakabayashi
- DNA Sequencing and Genomics Core, National Heart, Lung, and Blood Institute, National Institutes of Health, 20892 Bethesda, MD, United States
| | - Poching Liu
- DNA Sequencing and Genomics Core, National Heart, Lung, and Blood Institute, National Institutes of Health, 20892 Bethesda, MD, United States
| | - Kathy K Foxx
- Kalen Biomedical, LLC, 20886 Montgomery Village, MD, United States
| | - Howard S Kruth
- Experimental Atherosclerosis Section, Center for Molecular, National Heart, Lung, and Blood Institute , National Institutes of Health, 20892 Bethesda, MD, United States
| | - Xueting Jin
- Experimental Atherosclerosis Section, Center for Molecular, National Heart, Lung, and Blood Institute , National Institutes of Health, 20892 Bethesda, MD, United States
| | - Emile R Zakiev
- INSERM UMR_S 1166, Faculte de Medecine Pitie-Salpetriere, University of Pierre and Marie Curie - Paris 6, 75013 Paris, France
| | - Alexander N Orekhov
- Department of Biophysics, Biological Faculty, Moscow State University, Moscow 119991, Russian Federation
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Bobryshev YV, Nikiforov NG, Elizova NV, Orekhov AN. Macrophages and Their Contribution to the Development of Atherosclerosis. Results Probl Cell Differ 2017; 62:273-298. [PMID: 28455713 DOI: 10.1007/978-3-319-54090-0_11] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Atherosclerosis can be regarded as chronic inflammatory disease driven by lipid accumulation in the arterial wall. Macrophages play a key role in the development of local inflammatory response and atherosclerotic lesion growth. Atherosclerotic plaque is a complex microenvironment, in which different subsets of macrophages coexist executing distinct, although in some cases overlapping functions. According to the classical simplified nomenclature, lesion macrophages can belong to pro-inflammatory or anti-inflammatory or alternatively activated types. While the former promote the inflammatory response and participate in lipid accumulation, the latter are responsible for the inflammation resolution and plaque stabilisation. Atherosclerotic lesion dynamics depends therefore on the balance between these macrophages populations. The diverse functions of macrophages make them an attractive therapeutic target for the development of novel anti-atherosclerotic treatments. In this chapter, we discuss different types of macrophages and their roles in atherosclerotic lesion dynamics and describe the results of several experiments studying macrophage polarisation in atherosclerosis.
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Affiliation(s)
- Yuri V Bobryshev
- Faculty of Medicine, School of Medical Sciences, University of New South Wales, NSW, 2052, Sydney, Australia.
- School of Medicine, University of Western Sydney, Campbelltown, NSW, 2560, Australia.
- Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, 125315, Russia.
| | - Nikita G Nikiforov
- Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, 125315, Russia
- Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, 143025, Russia
| | - Natalia V Elizova
- Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, 125315, Russia
- Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, 143025, Russia
| | - Alexander N Orekhov
- Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, 125315, Russia
- Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, 143025, Russia
- Department of Biophysics, Biological Faculty, Moscow State University, Moscow, 119991, Russia
- National Research Center for Preventive Medicine, Moscow, 101000, Russia
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Pulanco MC, Cosman J, Ho MM, Huynh J, Fing K, Turcu J, Fraser DA. Complement Protein C1q Enhances Macrophage Foam Cell Survival and Efferocytosis. THE JOURNAL OF IMMUNOLOGY 2016; 198:472-480. [PMID: 27895181 DOI: 10.4049/jimmunol.1601445] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 11/01/2016] [Indexed: 12/12/2022]
Abstract
In the atherosclerotic lesion, macrophages ingest high levels of damaged modified low-density lipoproteins (LDLs), generating macrophage foam cells. Foam cells undergo apoptosis and, if not efficiently cleared by efferocytosis, can undergo secondary necrosis, leading to plaque instability and rupture. As a component of the innate immune complement cascade, C1q recognizes and opsonizes modified forms of LDL, such as oxidized or acetylated LDL, and promotes ingestion by macrophages in vitro. C1q was shown to be protective in an atherosclerosis model in vivo. Therefore, this study aimed to investigate whether ingestion of modified LDL in the presence of C1q alters macrophage foam cell survival or function. In an unbiased transcriptome analysis, C1q was shown to modulate expression of clusters of genes involved in cell death and apoptosis pathways in human monocyte-derived macrophages ingesting modified LDL; this was validated by quantitative PCR in human and murine macrophages. C1q downregulated levels and activity of active caspase-3 and PARP-1 in human and mouse macrophages during ingestion of modified LDL. This led to a measurable increase in survival and decrease in cell death, as measured by alamarBlue and propidium iodide assays, respectively. C1q opsonization also increased phagocytosis and efferocytosis in macrophage foam cells. These data suggest that C1q promotes macrophage survival during ingestion of excess cholesterol, as well as improves foam cell efferocytic function. This may be important in slowing disease progression and provides insight into the protective role of C1q in early atherosclerosis.
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Affiliation(s)
- Marc C Pulanco
- Department of Biological Sciences, California State University Long Beach, Long Beach, CA 90840
| | - Jason Cosman
- Department of Biological Sciences, California State University Long Beach, Long Beach, CA 90840
| | - Minh-Minh Ho
- Department of Biological Sciences, California State University Long Beach, Long Beach, CA 90840
| | - Jessica Huynh
- Department of Biological Sciences, California State University Long Beach, Long Beach, CA 90840
| | - Karina Fing
- Department of Biological Sciences, California State University Long Beach, Long Beach, CA 90840
| | - Jacqueline Turcu
- Department of Biological Sciences, California State University Long Beach, Long Beach, CA 90840
| | - Deborah A Fraser
- Department of Biological Sciences, California State University Long Beach, Long Beach, CA 90840
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Adiponectin reduces ER stress-induced apoptosis through PPARα transcriptional regulation of ATF2 in mouse adipose. Cell Death Dis 2016; 7:e2487. [PMID: 27882945 PMCID: PMC5260871 DOI: 10.1038/cddis.2016.388] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 10/21/2016] [Accepted: 10/25/2016] [Indexed: 12/29/2022]
Abstract
Adiponectin is a cytokine produced predominantly by adipose tissue and correlates with glucose and lipid homeostasis. However, the effects of adiponectin on endoplasmic reticulum (ER) stress and apoptosis of adipose tissue remain elusive. In this study, we found that tunicamycin-induced ER stress increased serum free fatty acid (FFA) and impaired glucose tolerance, elevated the mRNA levels of GRP78, Chop, ATF2 and caspase 3, but reduced adiponectin mRNA level in white adipose tissue. Moreover, ER stress-triggered adipocyte apoptosis by increasing cellular FFA level and Ca2+ level. Further analysis revealed that adiponectin alleviated ER stress-induced adipocyte apoptosis by elevating peroxisome proliferator-activated receptor alpha (PPARα) mRNA level. Our data also confirmed that adiponectin reduced early apoptotic cells and blocked the mitochondrial apoptosis pathway by activating the AdipoR1/AMP-activated protein kinase (AMPK) signal pathway. In addition, PPARα bound to ATF2 promoter region and inhibited transcription of ATF2. The inhibition of adipocyte apoptosis by adiponectin was correlated with transcriptional suppression of ATF2. Furthermore, adiponectin inhibited ER stress-induced apoptosis by activating the AMPK/PKC pathway. In summary, our data demonstrate adiponectin inhibited ER stress and apoptosis of adipocyte in vivo and in vitro by activating the AMPK/PPARα/ATF2 pathway. Our study establishes that adiponectin is an important adipocytokine for preventing and treating obesity.
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Abstract
The burden of type 2 diabetes and its major complication cardiovascular disease is rapidly increasing worldwide. Understanding the underlying pathogenic mechanisms of these diseases is crucial to develop novel therapeutics. Recent work using genetic and biochemical methods in mouse models and human samples have identified disturbed calcium signalling and endoplasmic reticulum stress as emerging factors involved in the pathogenesis of many metabolic diseases. In this review, we will highlight the specific roles of calcium signalling and endoplasmic reticulum stress response in the development of insulin resistance and atherosclerosis.
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Affiliation(s)
- L Ozcan
- Department of Medicine, Columbia University, New York, NY, USA.
| | - I Tabas
- Department of Medicine, Columbia University, New York, NY, USA.,Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.,Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
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Abstract
The remarkable plasticity and plethora of biological functions performed by macrophages have enticed scientists to study these cells in relation to atherosclerosis for >50 years, and major discoveries continue to be made today. It is now understood that macrophages play important roles in all stages of atherosclerosis, from initiation of lesions and lesion expansion, to necrosis leading to rupture and the clinical manifestations of atherosclerosis, to resolution and regression of atherosclerotic lesions. Lesional macrophages are derived primarily from blood monocytes, although recent research has shown that lesional macrophage-like cells can also be derived from smooth muscle cells. Lesional macrophages take on different phenotypes depending on their environment and which intracellular signaling pathways are activated. Rather than a few distinct populations of macrophages, the phenotype of the lesional macrophage is more complex and likely changes during the different phases of atherosclerosis and with the extent of lipid and cholesterol loading, activation by a plethora of receptors, and metabolic state of the cells. These different phenotypes allow the macrophage to engulf lipids, dead cells, and other substances perceived as danger signals; efflux cholesterol to high-density lipoprotein; proliferate and migrate; undergo apoptosis and death; and secrete a large number of inflammatory and proresolving molecules. This review article, part of the Compendium on Atherosclerosis, discusses recent advances in our understanding of lesional macrophage phenotype and function in different stages of atherosclerosis. With the increasing understanding of the roles of lesional macrophages, new research areas and treatment strategies are beginning to emerge.
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Affiliation(s)
- Ira Tabas
- From the Departments of Medicine (I.T.), Anatomy and Cell Biology (I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York; and the Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (K.E.B.) and Department of Pathology (K.E.B.), UW Diabetes Institute, University of Washington School of Medicine, Seattle
| | - Karin E Bornfeldt
- From the Departments of Medicine (I.T.), Anatomy and Cell Biology (I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York; and the Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (K.E.B.) and Department of Pathology (K.E.B.), UW Diabetes Institute, University of Washington School of Medicine, Seattle.
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Immune-inflammatory responses in atherosclerosis: Role of an adaptive immunity mainly driven by T and B cells. Immunobiology 2016; 221:1014-33. [PMID: 27262513 DOI: 10.1016/j.imbio.2016.05.010] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 05/06/2016] [Accepted: 05/23/2016] [Indexed: 01/22/2023]
Abstract
Adaptive immune response plays an important role in atherogenesis. In atherosclerosis, the proinflammatory immune response driven by Th1 is predominant but the anti-inflammatory response mediated mainly by regulatory T cells is also present. The role of Th2 and Th17 cells in atherogenesis is still debated. In the plaque, other T helper cells can be observed such as Th9 and Th22 but is little is known about their impact in atherosclerosis. Heterogeneity of CD4(+) T cell subsets presented in the plaque may suggest for plasticity of T cell that can switch the phenotype dependening on the local microenvironment and activating/blocking stimuli. Effector T cells are able to recognize self-antigens released by necrotic and apoptotic vascular cells and induce a humoral immune reaction. Tth cells resided in the germinal centers help B cells to switch the antibody class to the production of high-affinity antibodies. Humoral immunity is mediated by B cells that release antigen-specific antibodies. A variety of B cell subsets were found in human and murine atherosclerotic plaques. In mice, B1 cells could spontaneously produce atheroprotective natural IgM antibodies. Conventional B2 lymphocytes secrete either proatherogenic IgG, IgA, and IgE or atheroprotective IgG and IgM antibodies reactive with oxidation-specific epitopes on atherosclerosis-associated antigens. A small population of innate response activator (IRA) B cells, which is phenotypically intermediate between B1 and B2 cells, produces IgM but possesses proatherosclerotic properties. Finally, there is a minor subset of splenic regulatory B cells (Bregs) that protect against atherosclerotic inflammation through support of generation of Tregs and production of anti-inflammatory cytokines IL-10 and TGF-β and proapoptotic molecules.
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LaPensee CR, Mann JE, Rainey WE, Crudo V, Hunt SW, Hammer GD. ATR-101, a Selective and Potent Inhibitor of Acyl-CoA Acyltransferase 1, Induces Apoptosis in H295R Adrenocortical Cells and in the Adrenal Cortex of Dogs. Endocrinology 2016; 157:1775-88. [PMID: 26986192 DOI: 10.1210/en.2015-2052] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
ATR-101 is a novel, oral drug candidate currently in development for the treatment of adrenocortical cancer. ATR-101 is a selective and potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase 1 (ACAT1), an enzyme located in the endoplasmic reticulum (ER) membrane that catalyzes esterification of intracellular free cholesterol (FC). We aimed to identify mechanisms by which ATR-101 induces adrenocortical cell death. In H295R human adrenocortical carcinoma cells, ATR-101 decreases the formation of cholesteryl esters and increases FC levels, demonstrating potent inhibition of ACAT1 activity. Caspase-3/7 levels and terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeled-positive cells are increased by ATR-101 treatment, indicating activation of apoptosis. Exogenous cholesterol markedly potentiates the activity of ATR-101, suggesting that excess FC that cannot be adequately esterified increases caspase-3/7 activation and subsequent cell death. Inhibition of calcium release from the ER or the subsequent uptake of calcium by mitochondria reverses apoptosis induced by ATR-101. ATR-101 also activates multiple components of the unfolded protein response, an indicator of ER stress. Targeted knockdown of ACAT1 in an adrenocortical cell line mimicked the effects of ATR-101, suggesting that ACAT1 mediates the cytotoxic effects of ATR-101. Finally, in vivo treatment of dogs with ATR-101 decreased adrenocortical steroid production and induced cellular apoptosis that was restricted to the adrenal cortex. Together, these studies demonstrate that inhibition of ACAT1 by ATR-101 increases FC, resulting in dysregulation of ER calcium stores that result in ER stress, the unfolded protein response, and ultimately apoptosis.
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Affiliation(s)
- Christopher R LaPensee
- Departments of Internal Medicine (C.R.L., G.D.H.), Pathology (J.E.M.), and Molecular and Integrative Physiology (W.E.R., V.C.), University of Michigan, Ann Arbor, Michigan 48109; and Atterocor, Inc (S.W.H.), Ann Arbor, Michigan 48104
| | - Jacqueline E Mann
- Departments of Internal Medicine (C.R.L., G.D.H.), Pathology (J.E.M.), and Molecular and Integrative Physiology (W.E.R., V.C.), University of Michigan, Ann Arbor, Michigan 48109; and Atterocor, Inc (S.W.H.), Ann Arbor, Michigan 48104
| | - William E Rainey
- Departments of Internal Medicine (C.R.L., G.D.H.), Pathology (J.E.M.), and Molecular and Integrative Physiology (W.E.R., V.C.), University of Michigan, Ann Arbor, Michigan 48109; and Atterocor, Inc (S.W.H.), Ann Arbor, Michigan 48104
| | - Valentina Crudo
- Departments of Internal Medicine (C.R.L., G.D.H.), Pathology (J.E.M.), and Molecular and Integrative Physiology (W.E.R., V.C.), University of Michigan, Ann Arbor, Michigan 48109; and Atterocor, Inc (S.W.H.), Ann Arbor, Michigan 48104
| | - Stephen W Hunt
- Departments of Internal Medicine (C.R.L., G.D.H.), Pathology (J.E.M.), and Molecular and Integrative Physiology (W.E.R., V.C.), University of Michigan, Ann Arbor, Michigan 48109; and Atterocor, Inc (S.W.H.), Ann Arbor, Michigan 48104
| | - Gary D Hammer
- Departments of Internal Medicine (C.R.L., G.D.H.), Pathology (J.E.M.), and Molecular and Integrative Physiology (W.E.R., V.C.), University of Michigan, Ann Arbor, Michigan 48109; and Atterocor, Inc (S.W.H.), Ann Arbor, Michigan 48104
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Vazquez G, Solanki S, Dube P, Smedlund K, Ampem P. On the Roles of the Transient Receptor Potential Canonical 3 (TRPC3) Channel in Endothelium and Macrophages: Implications in Atherosclerosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 898:185-99. [PMID: 27161230 DOI: 10.1007/978-3-319-26974-0_9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In the cardiovascular and hematopoietic systems the Transient Receptor Potential Canonical 3 (TRPC3) channel has a well-recognized role in a number of signaling mechanisms that impact the function of diverse cells and tissues in physiology and disease. The latter includes, but is not limited to, molecular and cellular mechanisms associated to the pathogenesis of cardiac hypertrophy, hypertension and endothelial dysfunction. Despite several of these functions being closely related to atherorelevant mechanisms, the potential roles of TRPC3 in atherosclerosis, the major cause of coronary artery disease, have remained largely unexplored. Over recent years, a series of studies from the authors' laboratory revealed novel functions of TRPC3 in mechanisms related to endothelial inflammation, monocyte adhesion to endothelium and survival and apoptosis of macrophages. The relevance of these new TRPC3 functions to atherogenesis has recently began to receive validation through studies in mouse models of atherosclerosis with conditional gain or loss of TRPC3 function. This chapter summarizes these novel findings and provides a discussion of their impact in the context of atherosclerosis, in an attempt to delineate a framework for further exploration of this terra incognita in the TRPC field.
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Affiliation(s)
- Guillermo Vazquez
- Department of Physiology and Pharmacology, and Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Transverse Dr., UTHSC Mail stop 1008, Toledo, OH, 43614, USA.
| | - Sumeet Solanki
- Department of Physiology and Pharmacology, and Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Transverse Dr., UTHSC Mail stop 1008, Toledo, OH, 43614, USA
| | - Prabhatachandra Dube
- Department of Physiology and Pharmacology, and Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Transverse Dr., UTHSC Mail stop 1008, Toledo, OH, 43614, USA
| | - Kathryn Smedlund
- Department of Physiology and Pharmacology, and Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Transverse Dr., UTHSC Mail stop 1008, Toledo, OH, 43614, USA
| | - Prince Ampem
- Department of Physiology and Pharmacology, and Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Transverse Dr., UTHSC Mail stop 1008, Toledo, OH, 43614, USA
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Chmielewski S, Piaszyk-Borychowska A, Wesoly J, Bluyssen HAR. STAT1 and IRF8 in Vascular Inflammation and Cardiovascular Disease: Diagnostic and Therapeutic Potential. Int Rev Immunol 2015; 35:434-454. [DOI: 10.3109/08830185.2015.1087519] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Stefan Chmielewski
- Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
- Department of Nephrology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | - Anna Piaszyk-Borychowska
- Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
| | - Joanna Wesoly
- Laboratory of High Throughput Technologies, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
| | - Hans A. R. Bluyssen
- Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
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Bi SJ, Wang CY, Zhang J, Lv ZP, Li YX. Atorvastatin up-regulates TRIB3 independent of ATF4-CHOP pathway in atherosclerotic patients. Int J Clin Exp Med 2015; 8:21635-21640. [PMID: 26885117 PMCID: PMC4723962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Accepted: 10/27/2015] [Indexed: 06/05/2023]
Abstract
BACKGROUND Macrophage apoptosis triggered by endoplasmic reticulum (ER) stress contributes much to atherosclerosis, especially plaque vulnerability. Activating transcription factor 4 (ATF4)-CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP)-Tribbles 3 (TRIB3) pathway is closely related to the ER stress. This study aimed to investigate the effect of atorvastatin on the ATF4-CHOP-TRIB3 pathway. METHODS Forty-seven patients were randomized into 80-mg and 20-mg atorvastatin group. Follow-up was performed at weeks 6 and 12, and complete blood chemistry, lipid assay and detection of 5 target genes (tumor protein 53, ATF4, C/EBP, CHOP and TRIB3) in monocytes/macrophages were conducted. Furthermore, the interaction between dosage and duration of therapy was evaluated. RESULTS After 12-week therapy, patients in both groups experienced significant reductions in ATF4 (P=0.038) and C/EBP (P=0.003) expressions. Tumor protein 53 (P=0.015) and TRIB3 (P=0.045) expressions increased markedly in 80-mg atorvastatin group. However, there was no significant difference in CHOP expression at three time-points and between atorvastatin groups. Moreover, there was no interaction between dosage and duration of therapy. CONCLUSIONS Atorvastatin has an effect on ER stress through ATF4-CHOP pathway. Atorvastatin at a high dose is more likely to increase TRIB3 expression, but this warrants further investigation.
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Affiliation(s)
- Shao-Jie Bi
- Department of Cardiology, Second Hospital of Shandong UniversityJi’nan 250033, Shandong Province, China
| | - Chun-Yan Wang
- Department of Emergency Medicine, Second Hospital of Shandong UniversityJi’nan 250033, Shandong Province, China
| | - Juan Zhang
- Department of Cardiology, Second Hospital of Shandong UniversityJi’nan 250033, Shandong Province, China
| | - Zhao-Peng Lv
- Department of Cardiology, Second Hospital of Shandong UniversityJi’nan 250033, Shandong Province, China
| | - Yi-Xin Li
- Department of Radiology, Second Hospital of Shandong UniversityJi’nan 250033, Shandong Province, China
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Chang MT, Schwam ZG, Hajek MA, Paskhover B, Judson BL. Severe epistaxis due to aberrant vasculature in a patient with STAT-1 mutation. Head Neck 2015; 38:E68-70. [PMID: 26445901 DOI: 10.1002/hed.24165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Revised: 05/30/2015] [Accepted: 06/11/2015] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Signal transducer and activator 1 (STAT-1) mutations are rare and have been implicated in combined immunodeficiency, enhanced tumorigenesis, and vascular defects. METHODS A 60-year-old woman with a novel STAT-1 mutation and resulting immunodeficiency, squamous cell carcinoma, and vascular disease presented with profuse epistaxis secondary to rupture of an aberrant artery that she developed in part because of this mutation. After unsuccessful posterior packing, embolization was initiated but subsequently aborted because of a bovine origin carotid artery and a history of multiple carotid dissections. RESULTS After repeat posterior packing, hemostasis was achieved. No additional episodes of epistaxis occurred in the subsequent 13 months. CONCLUSION Vascular anomalies can present challenges in epistaxis management. In patients with conditions known to cause vascular anomalies, it is critical to obtain vascular imaging before intervention.
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Affiliation(s)
- Michael T Chang
- Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, Connecticut
| | - Zachary G Schwam
- Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, Connecticut
| | - Michael A Hajek
- Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, Connecticut
| | - Boris Paskhover
- Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, Connecticut
| | - Benjamin L Judson
- Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, Connecticut
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