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Hans S, Zabetakis I, Lordan R. The potential cardioprotective bioactive compounds in fermented alcoholic beverages: Mechanisms, challenges, and opportunities in beer and wine. Nutr Res 2025; 133:108-126. [PMID: 39705911 DOI: 10.1016/j.nutres.2024.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 10/04/2024] [Accepted: 10/04/2024] [Indexed: 12/23/2024]
Abstract
Excessive alcohol consumption is detrimental to human health, and it is implicated in the development of heart disease, stroke, and cancer. However, the last few decades have given rise to epidemiological evidence suggesting that low-to-moderate consumption of red wine and beer may reduce the risk of cardiovascular diseases. Studies have shown that moderate consumption of wine and beer protects against ischemic stroke, increases HDL plasma concentrations, and reduces platelet aggregation and insulin resistance. This cardioprotective effect has previously been attributed to phytochemicals in these beverages. This narrative review explores these potential cardioprotective phytochemicals and the underlying mechanisms responsible. Data from trials investigating the effect of alcoholic beverage consumption and in vitro analyses of the bioactive phytochemical compounds are reviewed. The potential of dealcoholized beverages is also explored. The literature shows that the cardioprotective effects observed with moderate alcohol consumption are mainly owing to the presence of anti-inflammatory polyphenolic and bioactive substances including lipophilic molecules present in low but biologically significant quantities. These phytochemicals are obtained from the raw materials and generated during the brewing processes. Studies indicate that dealcoholized variants of beer and wine also possess beneficial health effects, indicating that these effects are not alcohol dependent. There is also growing interest in dealcoholized beverages that are fortified or enhanced with cardioprotective properties. The development of such beverages is an important avenue of future research so that there are options for consumers who wish to enjoy wine and beer safely.
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Affiliation(s)
- Sakshi Hans
- Department of Biological Sciences, University of Limerick, Limerick, Ireland; Bernal Institute, University of Limerick, Limerick, Ireland
| | - Ioannis Zabetakis
- Department of Biological Sciences, University of Limerick, Limerick, Ireland; Bernal Institute, University of Limerick, Limerick, Ireland; Health Research Institute, University of Limerick, Limerick, Ireland
| | - Ronan Lordan
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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2
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Zhang X, Feng H, Han Y, Yuan X, Jiang M, Wang W, Gao L. Plaque Stabilization and Regression, from Mechanisms to Surveillance and Clinical Strategies. Rev Cardiovasc Med 2024; 25:459. [PMID: 39742242 PMCID: PMC11683705 DOI: 10.31083/j.rcm2512459] [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: 04/25/2024] [Revised: 07/13/2024] [Accepted: 08/02/2024] [Indexed: 01/03/2025] Open
Abstract
With advances in therapies to reduce cardiovascular events and improvements in coronary imaging, an increasing number of clinical trials have demonstrated that treatments to reduce cardiovascular events in coronary artery disease are associated with favorable effects on atherosclerotic plaque size and characteristics. It has been observed that various drugs may induce plaque regression and enhance plaque stability after plaque formation. Numerous clinical trials have been conducted to verify the occurrence of plaque stabilization and regression and their beneficial effects on cardiovascular events. Using invasive imaging techniques such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT), researchers have been able to gather evidence supporting the existence of coronary plaque stabilization and regression. In this review, we explore the possible mechanisms of plaque stabilization and regression, summarize the imaging features of plaque stabilization and regression, and assemble the evidence from clinical studies that have used different features as observational endpoints.
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Affiliation(s)
- Xi Zhang
- Senior Department of Cardiology, Sixth Medical Center of Chinese PLA General Hospital, 100853 Beijing, China
- Medical School of Chinese PLA, 100853 Beijing, China
| | - Huanhuan Feng
- Medical School of Chinese PLA, 100853 Beijing, China
- Emergency Department, First Medical Center of Chinese PLA General Hospital, 100853 Beijing, China
| | - Yan Han
- Senior Department of Cardiology, Sixth Medical Center of Chinese PLA General Hospital, 100853 Beijing, China
- Medical School of Chinese PLA, 100853 Beijing, China
| | - Xiaohang Yuan
- Senior Department of Cardiology, Sixth Medical Center of Chinese PLA General Hospital, 100853 Beijing, China
- Medical School of Chinese PLA, 100853 Beijing, China
| | - Mengting Jiang
- Senior Department of Cardiology, Sixth Medical Center of Chinese PLA General Hospital, 100853 Beijing, China
- Medical School of Chinese PLA, 100853 Beijing, China
| | - Wei Wang
- Senior Department of Cardiology, Sixth Medical Center of Chinese PLA General Hospital, 100853 Beijing, China
| | - Lei Gao
- Senior Department of Cardiology, Sixth Medical Center of Chinese PLA General Hospital, 100853 Beijing, China
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3
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Khattib A, Shmet M, Ashkar R, Hayek T, Khatib S. Novel bioactive lipids enhanced HDL-mediated cholesterol efflux from macrophages through the ABCA1 receptor pathway. Chem Phys Lipids 2024; 258:105367. [PMID: 38103770 DOI: 10.1016/j.chemphyslip.2023.105367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/13/2023] [Accepted: 12/12/2023] [Indexed: 12/19/2023]
Abstract
High-density lipoprotein (HDL) has traditionally been acknowledged as "good cholesterol" owing to its significant association with a decreased risk of atherosclerosis. This association is primarily attributed to HDL's direct involvement in cholesterol efflux capacity, which plays a pivotal role in reverse cholesterol transport. A novel active compound from Nannochloropsis microalgae termed lyso-DGTS, a lipid that contains EPA fatty acids, was previously isolated and found to increase paraoxonase 1 activity and enhance HDL-mediated cholesterol efflux and HDL-induced endothelial nitric oxide release. Here, the effect of different lyso-DGTS derivatives and analogs on HDL-mediated cholesterol efflux from macrophages was examined, and the mechanism was explored. Structure-activity relationships were established to characterize the essential lipid moieties responsible for HDL-mediated cholesterol efflux from macrophages. Lyso-DGTS, 1-carboxy-N-N-N-trimethyl-3-oleamidopropan-1-aminium, and lyso-platelet-activating factor increased HDL-mediated cholesterol efflux from macrophages dose-dependently, mainly via the ABCA1-mediated cholesterol efflux pathway. The effect of lyso-DGTS derivatives and analogs on the surface polarity of HDL was examined using the Laurdan generalized polarization (GP) assay. A reverse Pearson linear regression was obtained between Laurdan GP values and HDL-mediated cholesterol efflux. Because the incorporation of bioactive lipids into the surface phospholipid layer of HDL leads to a decrease in Laurdan GP, these bioactive lipids may induce lower phospholipid ordering and greater free space on the HDL particle surface, thereby enhancing apolipoprotein A1 binding to the ABCA1 receptor and improving ABCA1 cholesterol-mediated efflux. Our findings suggest a beneficial effect of lyso-DGTS and its bioactive lipid derivatives on increasing HDL-mediated cholesterol efflux activity from macrophages, which may impact atherosclerosis attenuation.
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Affiliation(s)
- Ali Khattib
- Natural Products and Analytical Chemistry Laboratory, MIGAL - Galilee Research Institute, Kiryat Shemona, Israel; Department of Biotechnology, Tel-Hai College, Israel; The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel
| | - Manar Shmet
- Natural Products and Analytical Chemistry Laboratory, MIGAL - Galilee Research Institute, Kiryat Shemona, Israel; Department of Biotechnology, Tel-Hai College, Israel
| | - Rasha Ashkar
- Natural Products and Analytical Chemistry Laboratory, MIGAL - Galilee Research Institute, Kiryat Shemona, Israel; Department of Biotechnology, Tel-Hai College, Israel
| | - Tony Hayek
- The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel
| | - Soliman Khatib
- Natural Products and Analytical Chemistry Laboratory, MIGAL - Galilee Research Institute, Kiryat Shemona, Israel; Department of Biotechnology, Tel-Hai College, Israel.
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Zhang J, Tang Z, Jiang J, Huang S, Zeng H, Gu J, Wang C, Zhang H. Clinical and Prognostic Value of Non-Fasting Lipoproteins and Apolipoproteins in Chinese Patients with Coronary Heart Disease. Rev Cardiovasc Med 2023; 24:314. [PMID: 39076452 PMCID: PMC11272848 DOI: 10.31083/j.rcm2411314] [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: 02/26/2023] [Revised: 05/10/2023] [Accepted: 05/17/2023] [Indexed: 07/31/2024] Open
Abstract
Background Lipid profiles differ naturally between individuals and between populations. So far, the data relating to non-fasting lipid profiles has been derived predominantly from studies on Western population. The characteristics and clinical significance of non-fasting lipids in Chinese patients with coronary heart disease (CHD) in response to traditional Chinese diets remain poorly understood. Methods A total of 1022 Chinese CHD patients with coronary artery luminal stenosis > 40% as diagnosed by coronary artery angiography were enrolled in the study. All patients received standard treatment for CHD, including statins. They were divided into an intermediate stenosis group (luminal stenosis 40-70%, n = 486) or a severe stenosis group (luminal stenosis > 70%, n = 536). Their blood lipid profiles were measured in the fasting state, and 4 hours after normal breakfast. All participants were followed up for five years. Major adverse cardiovascular events (MACE) including all-cause death, cardiac death, myocardial infarction, unscheduled coronary revascularization and stroke were recorded. Results After normal breakfast intake, patients with intermediate or severe stenosis showed an apparent increase in the levels of triglyceride (TG), remnant cholesterol (RC) and Apo (apolipoprotein) A1 compared to the fasting state, but a significant reduction in the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), Apo B and Apo E. In addition to the traditional risk factors (older age, male, diabetes and smoking) and coronary artery stenosis, the fasting levels of LDL-C and Apo B, as well as non-fasting levels of HDL-C and Apo A1, were identified as independent predictors of 5-year MACE occurrence by multivariate Cox proportional hazards analysis. Patients in the 1st tertile of the non-fasting HDL-C group ( < 0.86 mmol/L) showed a significantly higher risk of MACE than 3rd tertile ( > 1.07 mmol/L) (1st tertile: 2.786, 95% CI (confidence intervals) [1.808, 4.293], p < 0.001). Conclusions This prospective observational study found that lipid profiles in either the fasting or non-fasting states were associated with the long-term risk of MACE in Chinese CHD patients. In addition to the fasting LDL-C level, a low non-fasting HDL-C level may also be an independent risk factors for cardiovascular events. Measurement of lipid profiles during the non-fasting state may be feasible for the management of CHD patients in routine clinical practice in China.
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Affiliation(s)
- Junfeng Zhang
- Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 200011 Shanghai, China
| | - Zhengde Tang
- Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 200011 Shanghai, China
| | - Jintong Jiang
- Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 200011 Shanghai, China
| | - Shuying Huang
- Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 200011 Shanghai, China
| | - Huasu Zeng
- Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 200011 Shanghai, China
| | - Jun Gu
- Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 200011 Shanghai, China
| | - Changqian Wang
- Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 200011 Shanghai, China
| | - Huili Zhang
- Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 200011 Shanghai, China
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Abedi F, Sadeghi M, Omidkhoda N, Kelesidis T, Ramezani J, Samadi S, Mohammadpour AH. HDL-cholesterol concentration and its association with coronary artery calcification: a systematic review and meta-analysis. Lipids Health Dis 2023; 22:60. [PMID: 37158895 PMCID: PMC10165789 DOI: 10.1186/s12944-023-01827-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 04/29/2023] [Indexed: 05/10/2023] Open
Abstract
BACKGROUND Coronary artery calcification (CAC) is a potential risk marker of coronary atherosclerosis that has high specificity and sensitivity. However, the association between high-density lipoprotein cholesterol (HDL-C) concentration and CAC incidence and progression is controversial. METHODS PubMed, Embase, Web of Science, and Scopus were systematically searched to identify relevant observational studies up to March 2023 and assessed the methodological quality using Newcastle-Ottawa Scale (NOS) scale. Random-effects meta-analysis was used to estimate pooled odds ratios (OR) and 95% confidence interval considering heterogeneity across studies. RESULTS Of the 2,411 records, 25 cross-sectional (n = 71,190) and 13 cohort (n = 25,442) studies were included in the systematic review. Ten cross-sectional and eight cohort studies were not eligible and were omitted from the meta-analysis. A total of 15 eligible cross-sectional studies (n = 33,913) were included in the meta-analysis and pooled results revealed no significant association between HDL-C and CAC > 0, CAC > 10, or CAC > 100 [pooled OR: 0.99 (0.97, 1.01)]. Meta-analysis of the 5 eligible prospective cohort studies (n = 10,721) revealed no significant protective effect of high HDL-C against CAC > 0 [pooled OR: 1.02 (0.93, 1.13)]. CONCLUSIONS According to this analysis of observational studies, high HDL-C levels were not found to predict protection against CAC. These results suggest HDL quality rather than HDL quantity is important for certain aspects of atherogenesis and CAC. REGISTRATION NUMBER CRD42021292077.
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Affiliation(s)
- Farshad Abedi
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Masoumeh Sadeghi
- Department of Epidemiology, Faculty of Health, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Navid Omidkhoda
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Theodoros Kelesidis
- Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Javad Ramezani
- Department of Cardiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sara Samadi
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Amir Hooshang Mohammadpour
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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6
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Gasbarrino K, Hafiane A, Gianopoulos I, Zheng H, Mantzoros CS, Daskalopoulou SS. Relationship between circulating adipokines and cholesterol efflux in subjects with severe carotid atherosclerosis. Metabolism 2023; 140:155381. [PMID: 36566801 DOI: 10.1016/j.metabol.2022.155381] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/02/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022]
Abstract
AIMS Cholesterol efflux capacity (CEC) as a measure of high-density lipoprotein functionality is independently and inversely associated with increased risk of cardiovascular events and mortality, and advanced plaque morphology. Adipokines, adipose tissue-derived factors, can influence systemic lipoprotein metabolism, and participate in the regulation of vascular function and inflammation. We aimed to investigate the association between CEC and circulating adipokine levels (anti-inflammatory adiponectin, and pro-inflammatory chemerin and resistin) in subjects with severe carotid atherosclerotic disease and evaluate its impact on post-surgical outcomes. METHODS AND RESULTS This is a cross-sectional study with a 5-year follow-up component. Consecutive patients with severe carotid atherosclerosis scheduled for a carotid endarterectomy were recruited from hospital-based centres in Montreal, Canada (n = 285). Fasting blood samples were collected pre-operatively and used to measure plasma total and high-molecular weight (HMW) adiponectin, chemerin, and resistin, and to perform cholesterol efflux assays in J774 macrophage-like cells. Five-year post-surgery outcomes were obtained through medical chart review. Subjects had a mean age of 70.1 ± 9.4, were 67.0 % male, had various comorbidities (hypercholesterolemia [85.3 %], hypertension [83.5 %], type 2 diabetes [34.5 %], coronary artery disease [38.6 %]), and previously experienced cerebrovascular symptomatology (77.9 %). CEC was independently and positively associated with total and HMW adiponectin levels (ß [95 % confidence interval]; 0.216 [0.134-0.298] and 0.107 [0.037-0.176], respectively) but not with chemerin or resistin. Total adiponectin had the greatest association accounting for 8.3 % of the variance in CEC. Interaction regression models demonstrated a significant interaction between adiponectin and chemerin in increasing CEC. Notably, with each unit increase in CEC there was a 93.9 % decrease in the odds of having an ischemic cerebrovascular event 5 years post-surgery (0.061 [0.007-0.561]). CONCLUSIONS Our findings demonstrated circulating adiponectin to have a strong association with increased CEC in subjects with severe carotid atherosclerosis and high CEC to be associated with more favourable post-surgical outcomes. These findings reflect the importance of adipose tissue health in influencing CEC levels and atherosclerotic cardiovascular disease risk.
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Affiliation(s)
- Karina Gasbarrino
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University Montreal, Canada
| | - Anouar Hafiane
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University Montreal, Canada
| | - Ioanna Gianopoulos
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University Montreal, Canada
| | - Huaien Zheng
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University Montreal, Canada
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Section of Endocrinology, Diabetes and Metabolism, Boston VA Healthcare System, Boston, MA, United States
| | - Stella S Daskalopoulou
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University Montreal, Canada; Division of Internal Medicine, Department of Medicine, Faculty of Medicine, McGill University Health Centre, McGill University Montreal, Canada.
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Lyso-DGTS Lipid Derivatives Enhance PON1 Activities and Prevent Oxidation of LDL: A Structure–Activity Relationship Study. Antioxidants (Basel) 2022; 11:antiox11102058. [PMID: 36290781 PMCID: PMC9598486 DOI: 10.3390/antiox11102058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/14/2022] [Accepted: 10/14/2022] [Indexed: 11/22/2022] Open
Abstract
Paraoxonase 1 (PON1) plays a role in regulating reverse cholesterol transport and has antioxidative, anti-inflammatory, antiapoptotic, vasodilative, and antithrombotic activities. Scientists are currently focused on the modulation of PON1 expression using different pharmacological, nutritional, and lifestyle approaches. We previously isolated a novel active compound from Nannochloropsis microalgae—lyso-diacylglyceryltrimethylhomoserine (lyso-DGTS)—which increased PON1 activity, HDL-cholesterol efflux, and endothelial nitric oxide release. Here, to explore this important lipid moiety’s effect on PON1 activities, we examined the effect of synthesized lipid derivatives and endogenous analogs of lyso-DGTS on PON1 lactonase and arylesterase activities and LDL oxidation using structure–activity relationship (SAR) methods. Six lipids significantly elevated recombinant PON1 (rePON1) lactonase activity in a dose-dependent manner, and four lipids significantly increased rePON1 arylesterase activity. Using tryptophan fluorescence-quenching assay and a molecular docking method, lipid–PON1 interactions were characterized. An inverse correlation was obtained between the lactonase activity of PON1 and the docking energy of the lipid–PON1 complex. Furthermore, five of the lipids increased the LDL oxidation lag time and inhibited its propagation. Our findings suggest a beneficial effect of lyso-DGTS or lyso-DGTS derivatives through increased PON1 activity and prevention of LDL oxidation.
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Jiang M, Ding H, Huang Y, Wang L. Shear Stress and Metabolic Disorders-Two Sides of the Same Plaque. Antioxid Redox Signal 2022; 37:820-841. [PMID: 34148374 DOI: 10.1089/ars.2021.0126] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Significance: Shear stress and metabolic disorder are the two sides of the same atherosclerotic coin. Atherosclerotic lesions are prone to develop at branches and curvatures of arteries, which are exposed to oscillatory and low shear stress exerted by blood flow. Meanwhile, metabolic disorders are pivotal contributors to the formation and advancement of atherosclerotic plaques. Recent Advances: Accumulated evidence has provided insight into the impact and mechanisms of biomechanical forces and metabolic disorder on atherogenesis, in association with mechanotransduction, epigenetic regulation, and so on. Moreover, recent studies have shed light on the cross talk between the two drivers of atherosclerosis. Critical Issues: There are extensive cross talk and interactions between shear stress and metabolic disorder during the pathogenesis of atherosclerosis. The communications may amplify the proatherogenic effects through increasing oxidative stress and inflammation. Nonetheless, the precise mechanisms underlying such interactions remain to be fully elucidated as the cross talk network is considerably complex. Future Directions: A better understanding of the cross talk network may confer benefits for a more comprehensive clinical management of atherosclerosis. Critical mediators of the cross talk may serve as promising therapeutic targets for atherosclerotic vascular diseases, as they can inhibit effects from both sides of the plaque. Hence, further in-depth investigations with advanced omics approaches are required to develop novel and effective therapeutic strategies against atherosclerosis. Antioxid. Redox Signal. 37, 820-841.
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Affiliation(s)
- Minchun Jiang
- Heart and Vascular Institute, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Huanyu Ding
- Heart and Vascular Institute, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yu Huang
- Heart and Vascular Institute, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Li Wang
- Heart and Vascular Institute, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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Effect of Low High-Density Lipoprotein Level on Endothelial Activation and Prothrombotic Processes in Coronary Artery Disease-A Pilot Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19148637. [PMID: 35886486 PMCID: PMC9316205 DOI: 10.3390/ijerph19148637] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 11/17/2022]
Abstract
High-density lipoproteins (HDL) play an important role in the prevention of atherosclerosis. The aim of the study was to assess the relationship between serum HDL-C concentration and proinflammatory/prothrombic activation in coronary artery disease (CAD) patients. The study group included 27 acute myocardial infarction (AMI) patients and 30 stable angina pectoris (SA) patients. The control group consisted of 23 people without cardiac symptoms. In the AMI and SA groups, a lower HDL-C and a higher LDL-C/HDL-C index were observed. The SA patients had lower total cholesterol, LDL-C, sE-selectin ligand, as well as higher triglycerides and CD40 concentration in comparison with both the control and AMI groups. A higher von Willebrand Factor and intercellular adhesion molecule-1 were found in both study groups. Low HDL-C concentration in the CAD patients may intensify pro-inflammatory endothelial activation and prothrombotic processes. A low concentration of HDL-C and a high value of the LDL-C/HDL-C index seem to be better indices of atherogenic processes than the LDL-C concentration alone.
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10
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Centonze G, Natalini D, Piccolantonio A, Salemme V, Morellato A, Arina P, Riganti C, Defilippi P. Cholesterol and Its Derivatives: Multifaceted Players in Breast Cancer Progression. Front Oncol 2022; 12:906670. [PMID: 35719918 PMCID: PMC9204587 DOI: 10.3389/fonc.2022.906670] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 04/15/2022] [Indexed: 11/13/2022] Open
Abstract
Cholesterol is an essential lipid primarily synthesized in the liver through the mevalonate pathway. Besides being a precursor of steroid hormones, bile acid, and vitamin D, it is an essential structural component of cell membranes, is enriched in membrane lipid rafts, and plays a key role in intracellular signal transduction. The lipid homeostasis is finely regulated end appears to be impaired in several types of tumors, including breast cancer. In this review, we will analyse the multifaceted roles of cholesterol and its derivatives in breast cancer progression. As an example of the bivalent role of cholesterol in the cell membrane of cancer cells, on the one hand, it reduces membrane fluidity, which has been associated with a more aggressive tumor phenotype in terms of cell motility and migration, leading to metastasis formation. On the other hand, it makes the membrane less permeable to small water-soluble molecules that would otherwise freely cross, resulting in a loss of chemotherapeutics permeability. Regarding cholesterol derivatives, a lower vitamin D is associated with an increased risk of breast cancer, while steroid hormones, coupled with the overexpression of their receptors, play a crucial role in breast cancer progression. Despite the role of cholesterol and derivatives molecules in breast cancer development is still controversial, the use of cholesterol targeting drugs like statins and zoledronic acid appears as a challenging promising tool for breast cancer treatment.
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Affiliation(s)
- Giorgia Centonze
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.,Interdepartmental Center of Research in Molecular Biotechnology, University of Torino, Torino, Italy
| | - Dora Natalini
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.,Interdepartmental Center of Research in Molecular Biotechnology, University of Torino, Torino, Italy
| | - Alessio Piccolantonio
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.,Interdepartmental Center of Research in Molecular Biotechnology, University of Torino, Torino, Italy
| | - Vincenzo Salemme
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.,Interdepartmental Center of Research in Molecular Biotechnology, University of Torino, Torino, Italy
| | - Alessandro Morellato
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.,Interdepartmental Center of Research in Molecular Biotechnology, University of Torino, Torino, Italy
| | - Pietro Arina
- University College London (UCL), Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom
| | - Chiara Riganti
- Interdepartmental Center of Research in Molecular Biotechnology, University of Torino, Torino, Italy.,Department of Oncology, University of Torino, Torino, Italy
| | - Paola Defilippi
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.,Interdepartmental Center of Research in Molecular Biotechnology, University of Torino, Torino, Italy
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11
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Sarmadi N, Poustchi H, Ali Yari F, Radmard AR, Karami S, Pakdel A, Shabani P, Khaleghian A. Anti-inflammatory function of apolipoprotein B-depleted plasma is impaired in non-alcoholic fatty liver disease. PLoS One 2022; 17:e0266227. [PMID: 35413066 PMCID: PMC9004768 DOI: 10.1371/journal.pone.0266227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 03/16/2022] [Indexed: 11/19/2022] Open
Abstract
Background
Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular events. HDL exerts various protective functions on the cardiovascular system including anti-inflammatory activity by suppressing adhesion molecules expression in inflammation-induced endothelial cells. This study was designed to search if the anti-inflammatory capacity of apolipoprotein B-depleted plasma (apoB-depleted plasma) is altered in NAFLD patients.
Methods
A total of 83 subjects including 42 NAFLD and 41 control subjects were included in this cross-sectional study. Anti-inflammatory function of HDL was determined as the ability of apoB-depleted plasma to inhibit tumor necrosis factor-α (TNF-α)-induced expression of adhesion molecules in human umbilical vein endothelial cells (HUVECs).
Results
Incubation of inflammation-stimulated HUVECs with the NAFLD patients’ apo-B depleted plasma led to higher levels of expression of adhesion molecules compared to the control subjects’ plasma samples, reflecting an impaired anti-inflammatory capacity of apoB-depleted plasma in the NAFLD patients. Impaired anti-inflammatory capacity of apoB-depleted plasma was correlated with fatty liver and obesity indices. After adjustment with obesity indices, the association of anti-inflammatory capacity of apoB-depleted plasma with NAFLD remained significant.
Conclusion
Impaired anti-inflammatory activity of apoB-depleted plasma was independently associated with NAFLD.
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Affiliation(s)
- Negar Sarmadi
- Department of Biochemistry, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Hossein Poustchi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ali Yari
- Department of Biochemistry, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Amir Reza Radmard
- Department of Radiology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Karami
- Department of Biochemistry, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Abbas Pakdel
- Department of Biochemistry, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Parisa Shabani
- Department of Biochemistry, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, United States of America
- * E-mail: (PS); (AK)
| | - Ali Khaleghian
- Department of Biochemistry, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
- * E-mail: (PS); (AK)
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12
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Hafiane A, Gianopoulos I, Sorci-Thomas MG, Daskalopoulou SS. Current models of apolipoprotein A-I lipidation by adenosine triphosphate binding cassette transporter A1. Curr Opin Lipidol 2022; 33:139-145. [PMID: 34581311 DOI: 10.1097/mol.0000000000000786] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW The primary cardioprotective function of high-density lipoprotein (HDL) is to remove excess cellular free cholesterol (FC) from peripheral tissues and deliver it to the liver. Here, we summarize recent research that examines apolipoprotein A-I (apoA-I) lipidation models by adenosine triphosphate binding cassette transporter A1 (ABCA1) and discuss its relevance in atherosclerotic cardiovascular disease (ASCVD). RECENT FINDINGS The first step in HDL formation involves the interaction between apoA-I and ABCA1, where ABCA1 mediates the removal of FC and phospholipids from lipid-laden macrophages to form discoidal nascent HDL (nHDL). However, there are currently no clear-cut systematic models that characterize HDL formation. A number of recent studies have investigated the importance of apoA-I C- and N-terminal domains required for optimal cholesterol efflux and nHDL production. Furthermore, functional ABCA1 is required for direct or indirect binding to apoA-I where ABCA1 dimer-monomer interconversion facilitates apoA-I lipidation from plasma membrane microdomains. Microparticles are also another lipid source for apoA-I solubilization into nHDL. SUMMARY ApoA-I and ABCA1 are key factors in macrophage-mediated cholesterol efflux and nHDL production. Understanding of the key steps in HDL formation may unlock the therapeutic potential of HDL and improve clinical management of ASCVD.
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Affiliation(s)
- Anouar Hafiane
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University, Montreal, Canada
| | - Ioanna Gianopoulos
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University, Montreal, Canada
| | - Mary G Sorci-Thomas
- Division of Endocrinology, Metabolism and Clinical Nutrition, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Stella S Daskalopoulou
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University, Montreal, Canada
- Division of Internal Medicine, Department of Medicine, Faculty of Medicine, McGill University Health Centre, McGill University Montreal, Montreal, Canada
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13
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Laplagne C, Ligat L, Foote J, Lopez F, Fournié JJ, Laurent C, Valitutti S, Poupot M. Self-activation of Vγ9Vδ2 T cells by exogenous phosphoantigens involves TCR and butyrophilins. Cell Mol Immunol 2021; 18:1861-1870. [PMID: 34183807 PMCID: PMC8237548 DOI: 10.1038/s41423-021-00720-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/04/2021] [Indexed: 12/22/2022] Open
Abstract
The high cytotoxic activity of Vγ9Vδ2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies. However, the molecular mechanism of their activation by phosphoantigens (PAgs) is not completely known. Many studies have depicted the mechanism of Vγ9Vδ2 T-cell activation by PAg-sensed accessory cells, such as immune presenting cells or tumor cells. In this study, we demonstrated that pure resting Vγ9Vδ2 T lymphocytes can self-activate through exogenous PAgs, involving their TCR and the butyrophilins BTN3A1 and BTN2A1. This is the first time that these three molecules, concurrently expressed at the plasma membrane of Vγ9Vδ2 T cells, have been shown to be involved together on the same and unique T cell during PAg activation. Moreover, the use of probucol to stimulate the inhibition of this self-activation prompted us to propose that ABCA-1 could be implicated in the transfer of exogenous PAgs inside Vγ9Vδ2 T cells before activating them through membrane clusters formed by γ9TCR, BTN3A1 and BTN2A1. The self-activation of Vγ9Vδ2 T cells, which leads to self-killing, can therefore participate in the failure of γδ T cell-based therapies with exogenous PAgs and should be taken into account.
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Affiliation(s)
- Chloé Laplagne
- Inserm UMR1037, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Université Toulouse III Paul-Sabatier, Toulouse, France
- ERL 5294 CNRS, Toulouse, France
| | - Laetitia Ligat
- Inserm UMR1037, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Université Toulouse III Paul-Sabatier, Toulouse, France
- ERL 5294 CNRS, Toulouse, France
| | - Juliet Foote
- Inserm UMR1037, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Université Toulouse III Paul-Sabatier, Toulouse, France
- ERL 5294 CNRS, Toulouse, France
| | - Frederic Lopez
- Inserm UMR1037, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Université Toulouse III Paul-Sabatier, Toulouse, France
- ERL 5294 CNRS, Toulouse, France
| | - Jean-Jacques Fournié
- Inserm UMR1037, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Université Toulouse III Paul-Sabatier, Toulouse, France
- ERL 5294 CNRS, Toulouse, France
| | - Camille Laurent
- Inserm UMR1037, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Université Toulouse III Paul-Sabatier, Toulouse, France
- ERL 5294 CNRS, Toulouse, France
- IUCT-O, Toulouse, France
| | - Salvatore Valitutti
- Inserm UMR1037, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Université Toulouse III Paul-Sabatier, Toulouse, France
- ERL 5294 CNRS, Toulouse, France
| | - Mary Poupot
- Inserm UMR1037, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France.
- Université Toulouse III Paul-Sabatier, Toulouse, France.
- ERL 5294 CNRS, Toulouse, France.
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14
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Stasi A, Franzin R, Fiorentino M, Squiccimarro E, Castellano G, Gesualdo L. Multifaced Roles of HDL in Sepsis and SARS-CoV-2 Infection: Renal Implications. Int J Mol Sci 2021; 22:5980. [PMID: 34205975 PMCID: PMC8197836 DOI: 10.3390/ijms22115980] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023] Open
Abstract
High-density lipoproteins (HDLs) are a class of blood particles, principally involved in mediating reverse cholesterol transport from peripheral tissue to liver. Omics approaches have identified crucial mediators in the HDL proteomic and lipidomic profile, which are involved in distinct pleiotropic functions. Besides their role as cholesterol transporter, HDLs display anti-inflammatory, anti-apoptotic, anti-thrombotic, and anti-infection properties. Experimental and clinical studies have unveiled significant changes in both HDL serum amount and composition that lead to dysregulated host immune response and endothelial dysfunction in the course of sepsis. Most SARS-Coronavirus-2-infected patients admitted to the intensive care unit showed common features of sepsis disease, such as the overwhelmed systemic inflammatory response and the alterations in serum lipid profile. Despite relevant advances, episodes of mild to moderate acute kidney injury (AKI), occurring during systemic inflammatory diseases, are associated with long-term complications, and high risk of mortality. The multi-faceted relationship of kidney dysfunction with dyslipidemia and inflammation encourages to deepen the clarification of the mechanisms connecting these elements. This review analyzes the multifaced roles of HDL in inflammatory diseases, the renal involvement in lipid metabolism, and the novel potential HDL-based therapies.
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Affiliation(s)
- Alessandra Stasi
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (R.F.); (M.F.)
| | - Rossana Franzin
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (R.F.); (M.F.)
| | - Marco Fiorentino
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (R.F.); (M.F.)
| | - Enrico Squiccimarro
- Department of Emergency and Organ Transplant (DETO), University of Bari, 70124 Bari, Italy;
- Cardio-Thoracic Surgery Department, Heart & Vascular Centre, Maastricht University Medical Centre (MUMC), 6229HX Maastricht, The Netherlands
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Science, University of Foggia, 71122 Foggia, Italy;
| | - Loreto Gesualdo
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (R.F.); (M.F.)
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15
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Xu Y, Ye H, Zhu Y, Du S, Xu G, Wang Q. The efficacy of mobile health in alleviating risk factors related to the occurrence and development of coronary heart disease: A systematic review and meta-analysis. Clin Cardiol 2021; 44:609-619. [PMID: 33724494 PMCID: PMC8119799 DOI: 10.1002/clc.23596] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/28/2021] [Accepted: 03/08/2021] [Indexed: 12/19/2022] Open
Abstract
The association between the efficacy of mobile health and the occurrence and development of coronary heart disease (CHD) is still unclear. Mobile health can alleviate the risk factors for CHD. PubMed, EMbase, Web of Science, The Cochrane Library, CNKI, WanFang, and VIP databases were searched from inception through May 28, 2020. Randomized controlled trials of the effect of mobile health in alleviating the risk factors of CHD's occurrence and development were included. Risks of bias were assessed by two independent reviewers by using the RevMan 5.3, GRADEpro, and RoB2.0 to generate findings. Meta-analyses were performed to investigate the effects of mobile health on risk factors for CHD. Subgroup analyses were conducted. Sixteen randomized controlled trials, including 3898 patients with CHD, were included. Meta-analysis results showed that mobile health can reduce BMI (mean difference [MD] = - 1.24, 95% CI = - 2.02 to - 0.45, p < .05), waist circumference (MD = - 4.40, 95% CI = - 4.72 to - 4.08, p < .00001), total cholesterol (TC) level (MD = - 0.43, 95% CI = - 0.64 to - 0.22, p < 0.00001), low-density lipoprotein cholesterol (LDL-C) level (MD = - 0.31, 95% CI = - 0.48 to - 0.15, p < .05), diastolic blood pressure (MD = - 2.01, 95% CI = - 3.40 to - 0.623, p < .05), and depression (MD = - 8.32, 95% CI = - 12.83 to - 3.81, p < .05) and increase high-density lipoprotein cholesterol level (MD = 0.16, 95% CI = 0.01 to 0.32, p < .05) with statistically significant differences. The results of subgroup analyses indicated that the simple mobile health intervention has more remarkable advantages in reducing BMI, TC, LDL-C, and systolic blood pressure than the complex mobile health intervention. Mobile health can alleviate the risk factors for CHD and has a certain effect on the prevention and recovery of CHD. Simple mobile health has a remarkable advantage. Limited by the quantity and quality of included studies, future research enrolling high-quality studies should be taken to verify the above conclusions.
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Affiliation(s)
- Yue Xu
- School of NursingNanjing university of Chinese MedicineNanjingJiangsu ProvinceChina
| | - Hui Ye
- School of NursingNanjing university of Chinese MedicineNanjingJiangsu ProvinceChina
| | - Yuan Zhu
- School of NursingNanjing university of Chinese MedicineNanjingJiangsu ProvinceChina
| | - Shizheng Du
- School of NursingNanjing university of Chinese MedicineNanjingJiangsu ProvinceChina
| | - Guihua Xu
- School of NursingNanjing university of Chinese MedicineNanjingJiangsu ProvinceChina
| | - Qing Wang
- School of NursingNanjing university of Chinese MedicineNanjingJiangsu ProvinceChina
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16
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Santos HO, Lavie CJ. Weight loss and its influence on high-density lipoprotein cholesterol (HDL-C) concentrations: A noble clinical hesitation. Clin Nutr ESPEN 2021; 42:90-92. [DOI: 10.1016/j.clnesp.2021.01.033] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/23/2020] [Accepted: 01/23/2021] [Indexed: 11/30/2022]
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17
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Omote K, Yokota I, Nagai T, Sakuma I, Nakagawa Y, Kamiya K, Iwata H, Miyauchi K, Ozaki Y, Hibi K, Hiro T, Fukumoto Y, Mori H, Hokimoto S, Ohashi Y, Ohtsu H, Ogawa H, Daida H, Iimuro S, Shimokawa H, Saito Y, Kimura T, Matsuzaki M, Nagai R, Anzai T. High-Density Lipoprotein Cholesterol and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Statins: An Observation from the REAL-CAD Study. J Atheroscler Thromb 2021; 29:50-68. [PMID: 33431716 PMCID: PMC8737079 DOI: 10.5551/jat.59881] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
AIM The association between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease (CAD) remains unclear. Thus, in this study, we sought to determine how HDL-C level after statin therapy is associated with cardiovascular events in stable CAD patients. METHODS From the REAL-CAD study which had shown the favorable prognostic effect of high-dose pitavastatin in stable CAD patients with low-density lipoprotein cholesterol (LDL-C) ＜120 mg/dL, 9,221 patients with HDL-C data at baseline and 6 months, no occurrence of primary outcome at 6 months, and reported non-adherence for pitavastatin, were examined. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months of randomization. Absolute difference and ratio of HDL-C levels were defined as (those at 6 months-at baseline) and (absolute difference/baseline)×100, respectively. RESULTS During a median follow-up period of 4.0 (IQR 3.2-4.7) years, the primary outcome occurred in 417 (4.5%) patients. The adjusted risk of all HDL-C-related variables (baseline value, 6-month value, absolute, and relative changes) for the primary outcome was not significant (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.91-1.08, HR 1.03, 95% CI 0.94-1.12, HR 1.05, 95% CI 0.98-1.12, and HR 1.08, 95% CI 0.94-1.24, respectively). Furthermore, adjusted HRs of all HDL-C-related variables remained non-significant for the primary outcome regardless of on-treatment LDL-C level at 6 months. CONCLUSIONS After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable CAD.
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Affiliation(s)
- Kazunori Omote
- Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University
| | - Isao Yokota
- Department of Biostatistics, Graduate School of Medicine, Hokkaido University
| | - Toshiyuki Nagai
- Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University
| | | | - Yoshihisa Nakagawa
- Department of Cardiovascular Medicine, Shiga University of Medical Science Hospital
| | - Kiwamu Kamiya
- Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University
| | - Hiroshi Iwata
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine
| | - Katsumi Miyauchi
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine
| | - Yukio Ozaki
- Department of Cardiology, Fujita Health University School of Medicine
| | - Kiyoshi Hibi
- Division of Cardiology, Yokohama City University Medical Center
| | - Takafumi Hiro
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine
| | - Yoshihiro Fukumoto
- Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine
| | - Hiroyoshi Mori
- Department of Cardiology, Showa University Fujigaoka Hospital
| | - Seiji Hokimoto
- Department of Cardiovascular Medicine, Kumamoto University Hospital
| | - Yasuo Ohashi
- Department of Integrated Science and Technology for Sustainable Society, Chuo University
| | - Hiroshi Ohtsu
- National Center for Global Health and Medicine, Center for Clinical Sciences
| | | | - Hiroyuki Daida
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine
| | | | - Hiroaki Shimokawa
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
| | | | - Takeshi Kimura
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
| | | | | | - Toshihisa Anzai
- Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University
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18
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Kudinov VA, Alekseeva OY, Torkhovskaya TI, Baskaev KK, Artyushev RI, Saburina IN, Markin SS. High-Density Lipoproteins as Homeostatic Nanoparticles of Blood Plasma. Int J Mol Sci 2020; 21:E8737. [PMID: 33228032 PMCID: PMC7699323 DOI: 10.3390/ijms21228737] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/14/2020] [Accepted: 11/15/2020] [Indexed: 02/07/2023] Open
Abstract
It is well known that blood lipoproteins (LPs) are multimolecular complexes of lipids and proteins that play a crucial role in lipid transport. High-density lipoproteins (HDL) are a class of blood plasma LPs that mediate reverse cholesterol transport (RCT)-cholesterol transport from the peripheral tissues to the liver. Due to this ability to promote cholesterol uptake from cell membranes, HDL possess antiatherogenic properties. This function was first observed at the end of the 1970s to the beginning of the 1980s, resulting in high interest in this class of LPs. It was shown that HDL are the prevalent class of LPs in several types of living organisms (from fishes to monkeys) with high resistance to atherosclerosis and cardiovascular disorders. Lately, understanding of the mechanisms of the antiatherogenic properties of HDL has significantly expanded. Besides the contribution to RCT, HDL have been shown to modulate inflammatory processes, blood clotting, and vasomotor responses. These particles also possess antioxidant properties and contribute to immune reactions and intercellular signaling. Herein, we review data on the structure and mechanisms of the pleiotropic biological functions of HDL from the point of view of their evolutionary role and complex dynamic nature.
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Affiliation(s)
- Vasily A. Kudinov
- Laboratory of Cell Biology and Developmental Pathology, FSBSI Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia;
- Experimental Drug Research and Production Department, Institute of Biomedical Chemistry, 119121 Moscow, Russia; (K.K.B.); (R.I.A.)
| | - Olga Yu. Alekseeva
- Cell Physiology Laboratory, Institute of Biomedical Problems, Russian Academy of Sciences, 123007 Moscow, Russia;
- Department of Biochemistry, People’s Friendship University (RUDN University), 117198 Moscow, Russia
| | - Tatiana I. Torkhovskaya
- Laboratory of Phospholipid Transport Systems and Nanomedicines, Institute of Biomedical Chemistry, 119121 Moscow, Russia;
| | - Konstantin K. Baskaev
- Experimental Drug Research and Production Department, Institute of Biomedical Chemistry, 119121 Moscow, Russia; (K.K.B.); (R.I.A.)
| | - Rafael I. Artyushev
- Experimental Drug Research and Production Department, Institute of Biomedical Chemistry, 119121 Moscow, Russia; (K.K.B.); (R.I.A.)
| | - Irina N. Saburina
- Laboratory of Cell Biology and Developmental Pathology, FSBSI Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia;
| | - Sergey S. Markin
- Clinical Research Department, Institute of Biomedical Chemistry, 119121 Moscow, Russia;
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19
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Belisario DC, Akman M, Godel M, Campani V, Patrizio MP, Scotti L, Hattinger CM, De Rosa G, Donadelli M, Serra M, Kopecka J, Riganti C. ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma. Cells 2020; 9:cells9030647. [PMID: 32155954 PMCID: PMC7140509 DOI: 10.3390/cells9030647] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 03/04/2020] [Accepted: 03/04/2020] [Indexed: 02/06/2023] Open
Abstract
The ATP Binding Cassette transporter B1 (ABCB1) induces chemoresistance in osteosarcoma, because it effluxes doxorubicin, reducing the intracellular accumulation, toxicity, and immunogenic cell death induced by the drug. The ATP Binding Cassette transporter A1 (ABCA1) effluxes isopentenyl pyrophosphate (IPP), a strong activator of anti-tumor Vγ9Vδ2 T-cells. Recruiting this population may represent an alternative strategy to rescue doxorubicin efficacy in ABCB1-expressing osteosarcoma. In this work, we analyzed how ABCA1 and ABCB1 are regulated in osteosarcoma, and if increasing the ABCA1-dependent activation of Vγ9Vδ2 T-cells could be an effective strategy against ABCB1-expressing osteosarcoma. We used 2D-cultured doxorubicin-sensitive human U-2OS and Saos-2 cells, their doxorubicin-resistant sublines (U-2OS/DX580 and Saos-2/DX580), and 3D cultures of U-2OS and Saos-2 cells. DX580-sublines and 3D cultures had higher levels of ABCB1 and higher resistance to doxorubicin than parental cells. Surprisingly, they had reduced ABCA1 levels, IPP efflux, and Vγ9Vδ2 T-cell-induced killing. In these chemo-immune-resistant cells, the Ras/Akt/mTOR axis inhibits the ABCA1-transcription induced by Liver X Receptor α (LXRα); Ras/ERK1/2/HIF-1α axis up-regulates ABCB1. Targeting the farnesylation of Ras with self-assembling nanoparticles encapsulating zoledronic acid (NZ) simultaneously inhibited both axes. In humanized mice, NZ reduced the growth of chemo-immune-resistant osteosarcomas, increased intratumor necro-apoptosis, and ABCA1/ABCB1 ratio and Vγ9Vδ2 T-cell infiltration. We suggest that the ABCB1highABCA1low phenotype is indicative of chemo-immune-resistance. We propose aminobisphosphonates as new chemo-immune-sensitizing tools against drug-resistant osteosarcomas.
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Affiliation(s)
- Dimas Carolina Belisario
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy; (D.C.B.); (M.A.); (M.G.); (J.K.)
| | - Muhlis Akman
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy; (D.C.B.); (M.A.); (M.G.); (J.K.)
| | - Martina Godel
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy; (D.C.B.); (M.A.); (M.G.); (J.K.)
| | - Virginia Campani
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy; (V.C.); (L.S.)
| | - Maria Pia Patrizio
- IRCCS Istituto Ortopedico Rizzoli, Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, via di Barbiano, 1/10, 40136 Bologna, Italy; (M.P.P.); (C.M.H.); (M.S.)
| | - Lorena Scotti
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy; (V.C.); (L.S.)
| | - Claudia Maria Hattinger
- IRCCS Istituto Ortopedico Rizzoli, Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, via di Barbiano, 1/10, 40136 Bologna, Italy; (M.P.P.); (C.M.H.); (M.S.)
| | - Giuseppe De Rosa
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy; (V.C.); (L.S.)
| | - Massimo Donadelli
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy;
| | - Massimo Serra
- IRCCS Istituto Ortopedico Rizzoli, Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, via di Barbiano, 1/10, 40136 Bologna, Italy; (M.P.P.); (C.M.H.); (M.S.)
| | - Joanna Kopecka
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy; (D.C.B.); (M.A.); (M.G.); (J.K.)
| | - Chiara Riganti
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy; (D.C.B.); (M.A.); (M.G.); (J.K.)
- Correspondence: ; Tel.: +39-0116705857
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20
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Tora G, Kim SH, Pi Z, Johnson JA, Jiang J, Phillips M, Lloyd J, Abell LM, Lu H, Locke G, Adam LP, Taylor DS, Yin X, Behnia K, Zhao L, Yang R, Basso M, Caporuscio C, Chen AY, Liu E, Kirshgessner T, Onorato JM, Ryan C, Traeger SC, Gordon D, Wexler RR, Finlay HJ. Identification of Reversible Small Molecule Inhibitors of Endothelial Lipase (EL) That Demonstrate HDL-C Increase In Vivo. J Med Chem 2020; 63:1660-1670. [PMID: 31990537 DOI: 10.1021/acs.jmedchem.9b01831] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12. Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.
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21
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Abstract
Cardiovascular disease, with atherosclerosis as the major underlying factor, remains the leading cause of death worldwide. It is well established that cholesterol ester-enriched foam cells are the hallmark of atherosclerotic plaques. Multiple lines of evidence support that enhancing foam cell cholesterol efflux by HDL (high-density lipoprotein) particles, the first step of reverse cholesterol transport (RCT), is a promising antiatherogenic strategy. Yet, excitement towards the therapeutic potential of manipulating RCT for the treatment of cardiovascular disease has faded because of the lack of the association between cardiovascular disease risk and what was typically measured in intervention trials, namely HDL cholesterol, which has an inconsistent relationship to HDL function and RCT. In this review, we will summarize some of the potential reasons for this inconsistency, update the mechanisms of RCT, and highlight conditions in which impaired HDL function or RCT contributes to vascular disease. On balance, the evidence still argues for further research to better understand how HDL functionality contributes to RCT to develop prevention and treatment strategies to reduce the risk of cardiovascular disease.
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Affiliation(s)
- Mireille Ouimet
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa Heart Institute, University of Ottawa, Canada (M.O.)
| | - Tessa J Barrett
- Division of Cardiology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.)
| | - Edward A Fisher
- Division of Cardiology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.)
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22
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Yan Y, Song D, Wu J, Wang J. Long Non-Coding RNAs Link Oxidized Low-Density Lipoprotein With the Inflammatory Response of Macrophages in Atherogenesis. Front Immunol 2020; 11:24. [PMID: 32082313 PMCID: PMC7003668 DOI: 10.3389/fimmu.2020.00024] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 01/07/2020] [Indexed: 12/15/2022] Open
Abstract
Atherosclerosis is characterized as a chronic inflammatory response to cholesterol deposition in arteries. Low-density lipoprotein (LDL), especially the oxidized form (ox-LDL), plays a crucial role in the occurrence and development of atherosclerosis by inducing endothelial cell (EC) dysfunction, attracting monocyte-derived macrophages, and promoting chronic inflammation. However, the mechanisms linking cholesterol accumulation with inflammation in macrophage foam cells are poorly understood. Long non-coding RNAs (lncRNAs) are a group of non-protein-coding RNAs longer than 200 nucleotides and are found to regulate the progress of atherosclerosis. Recently, many lncRNAs interfering with cholesterol deposition or inflammation were identified, which might help elucidate their underlying molecular mechanism or be used as novel therapeutic targets. In this review, we summarize and highlight the role of lncRNAs linking cholesterol (mainly ox-LDL) accumulation with inflammation in macrophages during the process of atherosclerosis.
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Affiliation(s)
- Youyou Yan
- Department of Cardiology, Second Hospital of Jilin University, Changchun, China
- Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, China
| | - Dandan Song
- Department of Clinical Laboratory, Second Hospital of Jilin University, Changchun, China
| | - Junduo Wu
- Department of Cardiology, Second Hospital of Jilin University, Changchun, China
| | - Junnan Wang
- Department of Cardiology, Second Hospital of Jilin University, Changchun, China
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23
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Loria AD, Dattilo V, Santoro D, Guccione J, De Luca A, Ciaramella P, Pirozzi M, Iaccino E. Expression of Serum Exosomal miRNA 122 and Lipoprotein Levels in Dogs Naturally Infected by Leishmania infantum: A Preliminary Study. Animals (Basel) 2020; 10:ani10010100. [PMID: 31936232 PMCID: PMC7023135 DOI: 10.3390/ani10010100] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 01/03/2020] [Accepted: 01/06/2020] [Indexed: 12/21/2022] Open
Abstract
Simple Summary The immunopathogenesis of leishmaniasis is not completely understood. Exosomes are extracellular vesicles produced by most eukaryotic cells, containing various molecular constituents with biological effects (e.g., proteins, peptides, RNA). They play an important role in cell-to-cell signaling. Recently, exosomal microRNA were demonstrated to be able to regulate gene expression and protein production in mammalian cells, serving as potential biomarkers of disease. The microRNA miR-122 is a biomarker of hepatic damage widely studied in mice in the course of Leishmania infection. Leishmania organisms can interfere with miR-122 production leading to a dysfunction in cholesterol metabolism ensuring its proliferation in the infected host. In this study, we suggest that such a phenomenon may also occur in dogs affected by Leishmania infection. Abstract Current knowledge on the role of exosomal microRNA (miRNA) in canine leishmaniasis (CL), with particular regards to the interaction between miR-122 and lipid alterations, is limited. The aim of this study was to isolate/characterize exosomes in canine serum and evaluate the expression of miR-122 in ten healthy and ten leishmaniotic dogs. Serum exosomes were isolated using a polymer-based kit, ExoQuick® and characterized by flow cytometry and transmission electron microscopy, whereas miR-122-5p expression was evaluated by quantitative reverse-transcriptase polymerase chain reaction. A significant decreased expression of exosomal miR-122-5p, decreased serum levels of high-density lipoproteins, and increased serum levels of low-density lipoproteins were seen in leishmaniotic dogs when compared with healthy dogs. These results suggest that hepatic dysfunctions induced by the parasite interfere with lipoprotein status. The decreased expression of exosomal miR122 represents an additional effect of Leishmania infection in dogs as in people.
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Affiliation(s)
- Antonio Di Loria
- Department of Veterinary Medicine and Animal Productions, University Federico II, 80130 Napoli, Italy; (J.G.); (P.C.)
- Correspondence: (A.D.L.); (D.S.)
| | - Vincenzo Dattilo
- Department of Health Sciences, Magna Graecia University, 88100 Catanzaro, Italy;
| | - Domenico Santoro
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610, USA
- Correspondence: (A.D.L.); (D.S.)
| | - Jacopo Guccione
- Department of Veterinary Medicine and Animal Productions, University Federico II, 80130 Napoli, Italy; (J.G.); (P.C.)
| | - Adriana De Luca
- Department of Veterinary Medicine and Animal Productions, University Federico II, 80130 Napoli, Italy; (J.G.); (P.C.)
| | - Paolo Ciaramella
- Department of Veterinary Medicine and Animal Productions, University Federico II, 80130 Napoli, Italy; (J.G.); (P.C.)
| | - Marinella Pirozzi
- Institute of Protein Biochemistry, National Research Council, 88100 Napoli, Italy;
| | - Enrico Iaccino
- Department of Experimental and Clinical Medicine Magna Graecia University, 88100 Catanzaro, Italy;
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Hafiane A, Gasbarrino K, Daskalopoulou SS. The role of adiponectin in cholesterol efflux and HDL biogenesis and metabolism. Metabolism 2019; 100:153953. [PMID: 31377319 DOI: 10.1016/j.metabol.2019.153953] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 07/29/2019] [Accepted: 07/30/2019] [Indexed: 12/27/2022]
Abstract
Cholesterol efflux is the initial step in the reverse cholesterol transport pathway by which excess cholesterol in peripheral cells is exported and subsequently packaged into high-density lipoprotein (HDL) particles. Adiponectin is the most abundantly secreted adipokine that possesses anti-inflammatory and vasculoprotective properties via interaction with transmembrane receptors, AdipoR1 and AdipoR2. Evidence suggests that low levels of adiponectin may be a useful marker for atherosclerotic disease. A proposed anti-atherogenic mechanism of adiponectin involves its ability to promote cholesterol efflux. We performed a systematic review of the role of adiponectin in cholesterol efflux and HDL biogenesis, and of the proteins and receptors believed to be implicated in this process. Nineteen eligible studies (7 clinical, 11 fundamental, 1 clinical + fundamental) were identified through Ovid Medline, Ovid Embase, and Pubmed, that support the notion that adiponectin plays a key role in promoting ABCA1-dependent cholesterol efflux and in modulating HDL biogenesis via activation of the PPAR-γ/LXR-α signalling pathways in macrophages. AdipoR1 and AdipoR2 are suggested to also be implicated in this process, however the data are conflicting/insufficient to establish any firm conclusions. Once the exact mechanisms are unravelled, adiponectin may be critical in defining future treatment strategies directed towards increasing HDL functionality and ultimately reducing atherosclerotic disease.
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Affiliation(s)
- Anouar Hafiane
- Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
| | - Karina Gasbarrino
- Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
| | - Stella S Daskalopoulou
- Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
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Vulnerable Plaque, Characteristics, Detection, and Potential Therapies. J Cardiovasc Dev Dis 2019; 6:jcdd6030026. [PMID: 31357630 PMCID: PMC6787609 DOI: 10.3390/jcdd6030026] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 07/21/2019] [Accepted: 07/24/2019] [Indexed: 12/16/2022] Open
Abstract
Plaque development and rupture are hallmarks of atherosclerotic vascular disease. Despite current therapeutic developments, there is an unmet necessity in the prevention of atherosclerotic vascular disease. It remains a challenge to determine at an early stage if atherosclerotic plaque will become unstable and vulnerable. The arrival of molecular imaging is receiving more attention, considering it allows for a better understanding of the biology of human plaque and vulnerabilities. Various plaque therapies with common goals have been tested in high-risk patients with cardiovascular disease. In this work, the process of plaque instability, along with current technologies for sensing and predicting high-risk plaques, is debated. Updates on potential novel therapeutic approaches are also summarized.
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26
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ABCA1 Agonist Mimetic Peptide CS-6253 Induces Microparticles Release From Different Cell Types by ABCA1-Efflux-Dependent Mechanism. Can J Cardiol 2019; 35:770-781. [PMID: 31151713 DOI: 10.1016/j.cjca.2019.02.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 02/18/2019] [Accepted: 02/18/2019] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Small peptides based on the C-terminal domain of apo E have recently been proposed as ATP-binding cassette transporter A1 (ABCA1) agonist with therapeutic potential. Previous work has shown that a novel synthetic peptide, CS-6253, acts synergistically with apolipoprotein A-I or alone to generate high-density lipoprotein (HDL) particles; we have also shown that cells can release microparticles (50-350 nm in apparent diameter) in an ABCA1- and apolipoprotein A-I-dependent manner. The purpose of this study was to explore the ability of a novel synthetic peptide CS-6253 to induce microparticle release from various cell lines in the process of HDL biogenesis. METHODS The effects of CS-6253 on microparticle formation through the ABCA1 transporter were examined in vitro using cell-based systems and pharmacologic manipulations. RESULTS In cell-based systems combined with fast performance liquid chromatography and nano-sight-tracking analysis, we show that ABCA1 and CS-6253 mediate and increase the production of microparticles containing cholesterol. CS-6253 in baby hamster kidney cells not expressing ABCA1 (baby hamster kidney mock cells) did not alter cholesterol removal across the plasma membrane in the absence of ABCA1 expression even at high concentrations. We report that CS-6253 is not cytotoxic. CONCLUSIONS The present study shows that CS-6253 generates cholesterol containing microparticles with size heterogeneity (100-350 nm) in an ABCA1-dependent manner. We show that microparticles contribute to cell cholesterol efflux from monocyte-macrophage cells. At high doses, CS-6253 is not able to extract cholesterol from cells not expressing ABCA1, indicating that CS-6253 requires ABCA1 cooperation for cholesterol mobilization. We conclude that CS-6253 is an ABCA1 agonist peptide that promotes cellular cholesterol efflux through HDL biogenesis and microparticle formation.
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27
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Johnson JA, Tora G, Pi Z, Phillips M, Yin X, Yang R, Zhao L, Chen AY, Taylor DS, Basso M, Rose A, Behnia K, Onorato J, Chen XQ, Abell LM, Lu H, Locke G, Caporuscio C, Galella M, Adam LP, Gordon D, Wexler RR, Finlay HJ. Sulfonylated Benzothiazoles as Inhibitors of Endothelial Lipase. ACS Med Chem Lett 2018; 9:1263-1268. [PMID: 30613337 DOI: 10.1021/acsmedchemlett.8b00424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 11/19/2018] [Indexed: 12/13/2022] Open
Abstract
Endothelial lipase (EL) selectively metabolizes high density lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL concentration in preclinical animal models and was targeted as a potential treatment of atherosclerosis. We describe the introduction of an α-sulfone moiety to a benzothiazole series of EL inhibitors resulting in increased potency versus EL. Optimization for selectivity versus hepatic lipase and pharmacokinetic properties resulted in the discovery of 24, which showed good in vitro potency and bioavailability but, unexpectedly, did not increase HDL in the mouse pharmacodynamic model at the target plasma exposure.
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28
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Estrada-Luna D, Ortiz-Rodriguez MA, Medina-Briseño L, Carreón-Torres E, Izquierdo-Vega JA, Sharma A, Cancino-Díaz JC, Pérez-Méndez O, Belefant-Miller H, Betanzos-Cabrera G. Current Therapies Focused on High-Density Lipoproteins Associated with Cardiovascular Disease. Molecules 2018; 23:molecules23112730. [PMID: 30360466 PMCID: PMC6278283 DOI: 10.3390/molecules23112730] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 10/20/2018] [Accepted: 10/21/2018] [Indexed: 02/06/2023] Open
Abstract
High-density lipoproteins (HDL) comprise a heterogeneous family of lipoprotein particles divided into subclasses that are determined by density, size and surface charge as well as protein composition. Epidemiological studies have suggested an inverse correlation between High-density lipoprotein-cholesterol (HDL-C) levels and the risk of cardiovascular diseases and atherosclerosis. HDLs promote reverse cholesterol transport (RCT) and have several atheroprotective functions such as anti-inflammation, anti-thrombosis, and anti-oxidation. HDLs are considered to be atheroprotective because they are associated in serum with paraoxonases (PONs) which protect HDL from oxidation. Polyphenol consumption reduces the risk of chronic diseases in humans. Polyphenols increase the binding of HDL to PON1, increasing the catalytic activity of PON1. This review summarizes the evidence currently available regarding pharmacological and alternative treatments aimed at improving the functionality of HDL-C. Information on the effectiveness of the treatments has contributed to the understanding of the molecular mechanisms that regulate plasma levels of HDL-C, thereby promoting the development of more effective treatment of cardiovascular diseases. For that purpose, Scopus and Medline databases were searched to identify the publications investigating the impact of current therapies focused on high-density lipoproteins.
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Affiliation(s)
- Diego Estrada-Luna
- Instituto Nacional de Cardiología "Ignacio Chávez" Juan Badiano No. 1, Belisario Domínguez Sección 16, 14080 Tlalpan, Mexico City, Mexico.
| | - María Araceli Ortiz-Rodriguez
- Facultad de Nutrición, Universidad Autónoma del Estado de Morelos, UAEM, Calle Río Iztaccihuatl S/N, Vista Hermosa, 62350 Cuernavaca, Morelos, Mexico.
| | - Lizett Medina-Briseño
- Universidad de la Sierra Sur, UNSIS, Miahuatlán de Porfirio Díaz, 70800 Oaxaca, Mexico.
| | - Elizabeth Carreón-Torres
- Instituto Nacional de Cardiología "Ignacio Chávez" Juan Badiano No. 1, Belisario Domínguez Sección 16, 14080 Tlalpan, Mexico City, Mexico.
| | - Jeannett Alejandra Izquierdo-Vega
- Área Académica de Medicina, Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Carretera Actopan-Tilcuautla, Ex-Hacienda La Concepción S/N, San Agustín Tlaxiaca, 42160 Hidalgo, Mexico.
| | - Ashutosh Sharma
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Epigmenio Gonzalez 500, 76130 Queretaro, Mexico.
| | - Juan Carlos Cancino-Díaz
- Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional, 11340 Ciudad de México, Mexico.
| | - Oscar Pérez-Méndez
- Instituto Nacional de Cardiología "Ignacio Chávez" Juan Badiano No. 1, Belisario Domínguez Sección 16, 14080 Tlalpan, Mexico City, Mexico.
| | | | - Gabriel Betanzos-Cabrera
- Área Académica de Medicina, Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Carretera Actopan-Tilcuautla, Ex-Hacienda La Concepción S/N, San Agustín Tlaxiaca, 42160 Hidalgo, Mexico.
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29
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Riganti C, Castella B, Massaia M. ABCA1, apoA-I, and BTN3A1: A Legitimate Ménage à Trois in Dendritic Cells. Front Immunol 2018; 9:1246. [PMID: 29937767 PMCID: PMC6002486 DOI: 10.3389/fimmu.2018.01246] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 05/17/2018] [Indexed: 12/11/2022] Open
Abstract
Human Vγ9Vδ2 T cells have the capacity to detect supra-physiological concentrations of phosphoantigens (pAgs) generated by the mevalonate (Mev) pathway of mammalian cells under specific circumstances. Isopentenyl pyrophosphate (IPP) is the prototypic pAg recognized by Vγ9Vδ2 T cells. B-cell derived tumor cells (i.e., lymphoma and myeloma cells) and dendritic cells (DCs) are privileged targets of Vγ9Vδ2 T cells because they generate significant amounts of IPP which can be boosted with zoledronic acid (ZA). ZA is the most potent aminobisphosphonate (NBP) clinically available to inhibit osteoclast activation and a very potent inhibitor of farnesyl pyrophosphate synthase in the Mev pathway. ZA-treated DCs generate and release in the supernatants picomolar IPP concentrations which are sufficient to induce the activation of Vγ9Vδ2 T cells. We have recently shown that the ATP-binding cassette transporter A1 (ABCA1) plays a major role in the extracellular release of IPP from ZA-treated DCs. This novel ABCA1 function is fine-tuned by physical interactions with IPP, apolipoprotein A-I (apoA-I), and butyrophilin-3A1 (BTN3A1). The mechanisms by which soluble IPP induces Vγ9Vδ2 T-cell activation remain to be elucidated. It is possible that soluble IPP binds to BTN3A1, apoA-I, or other unknown molecules on the cell surface of bystander cells like monocytes, NK cells, Vγ9Vδ2 T cells, or any other cell locally present. Investigating this scenario may represent a unique opportunity to further characterize the role of BTN3A1 and other molecules in the recognition of soluble IPP by Vγ9Vδ2 T cells.
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Affiliation(s)
- Chiara Riganti
- Dipartimento di Oncologia, Università degli Studi di Torino, Turin, Italy
| | - Barbara Castella
- Laboratorio di Immunologia dei Tumori del Sangue (LITS), Centro Interdipartimentale di Ricerca in Biologia Molecolare (CIRBM), Università degli Studi di Torino, Turin, Italy
| | - Massimo Massaia
- Laboratorio di Immunologia dei Tumori del Sangue (LITS), Centro Interdipartimentale di Ricerca in Biologia Molecolare (CIRBM), Università degli Studi di Torino, Turin, Italy.,SC Ematologia, AO S. Croce e Carle, Cuneo, Italy
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30
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Lin HC, Lii CK, Chen HC, Lin AH, Yang YC, Chen HW. Andrographolide Inhibits Oxidized LDL-Induced Cholesterol Accumulation and Foam Cell Formation in Macrophages. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2018; 46:87-106. [PMID: 29298513 DOI: 10.1142/s0192415x18500052] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
oxLDL is involved in the pathogenesis of atherosclerotic lesions through cholesterol accumulation in macrophage foam cells. Andrographolide, the bioactive component of Andrographis paniculata, possesses several biological activities such as anti-inflammatory, anti-oxidant, and anticancer functions. Scavenger receptors (SRs), including class A SR (SR-A) and CD36, are responsible for the internalization of oxLDL. In contrast, receptors for reverse cholesterol transport, including ABCA1 and ABCG1, mediate the efflux of cholesterol from macrophage foam cells. Transcription factor liver X receptor [Formula: see text] (LXR[Formula: see text] plays a key role in lipid metabolism and inflammation as well as in the regulation of ABCA1 and ABCG1 expression. Because of the contribution of inflammation to macrophage foam cell formation and the potent anti-inflammatory activity of andrographolide, we hypothesized that andrographolide might inhibit oxLDL-induced macrophage foam cell formation. The results showed that andrographolide reduced oxLDL-induced lipid accumulation in macrophage foam cells. Andrographolide decreased the mRNA and protein expression of CD36 by inducing the degradation of CD36 mRNA; however, andrographolide had no effect on SR-A expression. In contrast, andrographolide increased the mRNA and protein expression of ABCA1 and ABCG1, which were dependent on LXR[Formula: see text]. Andrographolide enhanced LXR[Formula: see text] nuclear translocation and DNA binding activity. Treatment with the LXR[Formula: see text] antagonist GGPP and transfection with LXR[Formula: see text] siRNA reversed the ability of andrographolide to stimulate ABCA1 and ABCG1 protein expression. In conclusion, inhibition of CD36-mediated oxLDL uptake and induction of ABCA1- and ABCG1-dependent cholesterol efflux are two working mechanisms by which andrographolide inhibits macrophage foam cell formation, which suggests that andrographolide could be a potential candidate to prevent atherosclerosis.
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Affiliation(s)
- Hung-Chih Lin
- Division of Neonatology, College of Medicine and Department of Pediatrics, Children’s Hospital of China Medical, University and China Medical University Hospital, Taichung, Taiwan
| | - Chong-Kuei Lii
- Department of Nutrition, China Medical University, Taichung, Taiwan
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan
| | - Hui-Chun Chen
- Department of Nutrition, China Medical University, Taichung, Taiwan
| | - Ai-Hsuan Lin
- Department of Nutrition, China Medical University, Taichung, Taiwan
| | - Ya-Chen Yang
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan
| | - Haw-Wen Chen
- Department of Nutrition, China Medical University, Taichung, Taiwan
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31
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Li D, Fawaz MV, Morin EE, Sviridov D, Ackerman R, Olsen K, Remaley AT, Schwendeman A. Effect of Synthetic High Density Lipoproteins Modification with Polyethylene Glycol on Pharmacokinetics and Pharmacodynamics. Mol Pharm 2018; 15:83-96. [PMID: 29141139 PMCID: PMC6435036 DOI: 10.1021/acs.molpharmaceut.7b00734] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Synthetic high density lipoprotein nanoparticles (sHDLs) capable of mobilizing excess cholesterol from atherosclerotic arteries and delivering it to the liver for elimination have been shown to reduce plaque burden in patients. Unfortunately, sHDLs have a narrow therapeutic index and relative to the endogenous HDL shorter circulation half-life. Surface modification with polyethylene glycol (PEG) was investigated for its potential to extend sHDL circulation in vivo. Various amounts (2.5, 5, and 10%) and different chain lengths (2 and 5 kDa) of PEG-modified lipids were incorporated in sHDL's lipid membrane. Incorporating PEG did not reduce the ability of sHDL to facilitate cholesterol efflux, nor did it inhibit cholesterol uptake by the liver cells. By either adding more PEG or using PEG of longer chain lengths, the circulation half-life was extended. Addition of PEG also increased the area under the curve for the phospholipid component of sHDL (p < 0.05), but not for the apolipoprotein A-I peptide component of sHDL, suggesting sHDL is remodeled by endogenous lipoproteins in vivo. The extended phospholipid circulation led to a higher mobilization of plasma free cholesterol, a biomarker for facilitation of reverse cholesterol transport. The area under the cholesterol mobilization increased about 2-4-fold (p < 0.05), with greater increases observed for longer PEG chains and higher molar percentages of incorporated PEGylated lipids. Mobilized cholesterol was associated primarily with the HDL fraction, led to a transient increase in VLDL cholesterol, and returned to baseline 24 h postdose. Overall, PEGylation of sHDL led to beneficial changes in sHDL particle pharmacokinetic and pharmacodynamic behaviors.
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Affiliation(s)
- Dan Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109
| | - Maria V. Fawaz
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109
| | - Emily E. Morin
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109
| | - Denis Sviridov
- National Heart, Lung and Blood Institute, National Institutes of Health, Building 10 – 2C433, 10 Center Drive, MSC 1666, Bethesda, MD 20892
| | - Rose Ackerman
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109
| | - Karl Olsen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109
| | - Alan T. Remaley
- National Heart, Lung and Blood Institute, National Institutes of Health, Building 10 – 2C433, 10 Center Drive, MSC 1666, Bethesda, MD 20892
| | - Anna Schwendeman
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109
- Biointerfaces Institute, University of Michigan, NCRC, 2800 Plymouth Road, Ann Arbor, MI 48109
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Kudinov VA, Zakharova TS, Torkhovskaya TI, Ipatova OM, Archakov AI. [Pharmacological targets for dislipidemies correction. Opportunities and prospects of therapeutic usage]. BIOMEDITSINSKAIA KHIMIIA 2018; 64:66-83. [PMID: 29460837 DOI: 10.18097/pbmc20186401066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Literature data on influence of existing and new groups of drug preparations for dyslipidemias correction are systemized, and molecular mechanisms of their effects are reviewed. The results of experimental and clinical investigations aimed at revealing of new pharmacological targets of dyslipidemias correction were analyzed. The approaches for activation of high density lipoproteins functionality are described. The implementation of alternative preparations with new alternative mechanisms of action may be suggested to improve the effectiveness of traditional treatment in the future.
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Affiliation(s)
- V A Kudinov
- Institute of Biomedical Chemistry, Moscow, Russia
| | | | | | - O M Ipatova
- Institute of Biomedical Chemistry, Moscow, Russia
| | - A I Archakov
- Institute of Biomedical Chemistry, Moscow, Russia
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33
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Abstract
PURPOSE OF REVIEW High-density lipoproteins (HDL) are thought to exert a protective role against atherosclerosis. The measurement of the cholesterol mass within HDL (HDL-C) represents a good biomarker of cardiovascular health, but HDL-C appears to be a poor therapeutic target. Here, we discuss new targets for the development of HDL-directed therapies. RECENT FINDINGS Among cardio-protective functions of HDL particles, the ability of HDL to remove cholesterol from cells involved in the early stages of atherosclerosis is considered one of the most important functions. This process, termed "HDL biogenesis," is initiated by the formation of highly specialized plasma membrane micro-domains by the ATP-binding cassette transporter A1 (ABCA1) and the binding of apolipoproteins (apo) such as apoA-I, the major protein moiety of HDL, to the micro-domains. Although early strategies aimed at increasing HDL biogenesis by upregulating ABCA1 or apoA-I gene expression have not met with clinical success, recent advances in understanding transcriptional, post-transcriptional, and post-translational regulatory pathways propose new targets for the promotion of HDL biogenesis. We have recently reported that a novel apoA-I-binding protein desmocollin 1 (DSC1) prevents HDL biogenesis and that inhibition of apoA-I-DSC1 interactions promotes HDL biogenesis by stabilizing ABCA1. This new HDL regulation pathway nominates DSC1 as an attractive pharmacological target. In the absence of clinically useful therapy to increase HDL biogenesis, finding novel targets to unlock the therapeutic potential of HDL is highly desired. Modulation of apoA-I-DSC1 interactions may be a viable strategy.
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Affiliation(s)
- Jacques Genest
- The Research Institute of the McGill University Health Center, 1001 boul. Decarie Bloc E, Office EM12212, Montreal, Québec, H4A 3J1, Canada
| | - Hong Y Choi
- The Research Institute of the McGill University Health Center, 1001 boul. Decarie Bloc E, Office EM12212, Montreal, Québec, H4A 3J1, Canada.
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Dysfunctional high-density lipoproteins have distinct composition, diminished anti-inflammatory potential and discriminate acute coronary syndrome from stable coronary artery disease patients. Sci Rep 2017; 7:7295. [PMID: 28779156 PMCID: PMC5544737 DOI: 10.1038/s41598-017-07821-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 07/03/2017] [Indexed: 12/25/2022] Open
Abstract
There is a stringent need to find means for risk stratification of coronary artery diseases (CAD) patients. We aimed at identifying alterations of plasma high-density lipoproteins (HDL) components and their validation as dysfunctional HDL that could discriminate between acute coronary syndrome (ACS) and stable angina (SA) patients. HDL2 and HDL3 were isolated from CAD patients’ plasma and healthy subjects. ApolipoproteinAI (apoAI), apoAII, apoCIII, malondialdehyde (MDA), myeloperoxidase (MPO), ceruloplasmin and paraoxonase1 (PON1) were assessed. The anti-inflammatory potential of HDL subfractions was tested by evaluating the secreted inflammatory molecules of tumor necrosis factor α-activated endothelial cells (EC) upon co-incubation with HDL2 or HDL3. We found in ACS versus SA patients: 40% increased MPO, MDA, apoCIII in HDL2 and HDL3, 35% augmented apoAII in HDL2, and in HDL3 increased ceruloplasmin, decreased apoAII (40%) and PON1 protein and activity (15% and 25%). Co-incubation of activated EC with HDL2 or HDL3 from CAD patients induced significantly increased levels of secreted inflammatory molecules, 15–20% more for ACS versus SA. In conclusion, the assessed panel of markers correlates with the reduced anti-inflammatory potential of HDL subfractions isolated from ACS and SA patients (mostly for HDL3 from ACS) and can discriminate between these two groups of CAD patients.
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35
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Castella B, Kopecka J, Sciancalepore P, Mandili G, Foglietta M, Mitro N, Caruso D, Novelli F, Riganti C, Massaia M. The ATP-binding cassette transporter A1 regulates phosphoantigen release and Vγ9Vδ2 T cell activation by dendritic cells. Nat Commun 2017; 8:15663. [PMID: 28580927 PMCID: PMC5465356 DOI: 10.1038/ncomms15663] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 04/19/2017] [Indexed: 12/21/2022] Open
Abstract
Vγ9Vδ2 T cells are activated by phosphoantigens, such as isopentenyl pyrophosphate (IPP), which is generated in the mevalonate pathway of antigen-presenting cells. IPP is released in the extracellular microenvironment via unknown mechanisms. Here we show that the ATP-binding cassette transporter A1 (ABCA1) mediates extracellular IPP release from dendritic cells (DC) in cooperation with apolipoprotein A-I (apoA-I) and butyrophilin-3A1. IPP concentrations in the supernatants are sufficient to induce Vγ9Vδ2 T cell proliferation after DC mevalonate pathway inhibition with zoledronic acid (ZA). ZA treatment increases ABCA1 and apoA-I expression via IPP-dependent LXRα nuclear translocation and PI3K/Akt/mTOR pathway inhibition. These results close the mechanistic gap in our understanding of extracellular IPP release from DC and provide a framework to fine-tune Vγ9Vδ2 T cell activation via mevalonate and PI3K/Akt/mTOR pathway modulation. γδT cells are activated by phosphoantigens, and ABCA1 is involved in cholesterol transport. Here the authors link these ideas to show that ABCA1, apoA-I and BTN3A1 regulate extracellular phosphoantigen release by dendritic cells, and implicate ABCA1 in mevalonate-mediated activation of Vγ9Vδ2 T cells.
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Affiliation(s)
- Barbara Castella
- Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Via Nizza 52, Torino 10126, Italy.,Centro di Ricerca in Medicina Sperimentale (CeRMS), AOU Città della Salute e della Scienza di Torino, Via Santena 5, Torino 10126, Italy
| | - Joanna Kopecka
- Dipartimento di Oncologia, Università degli Studi di Torino, Via Santena 5/bis, Torino 10126, Italy
| | - Patrizia Sciancalepore
- Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Via Nizza 52, Torino 10126, Italy.,Centro di Ricerca in Medicina Sperimentale (CeRMS), AOU Città della Salute e della Scienza di Torino, Via Santena 5, Torino 10126, Italy
| | - Giorgia Mandili
- Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Via Nizza 52, Torino 10126, Italy.,Centro Interdipartimentale di Ricerca per le Biotecnologie Molecolari (CIRBM), Via Nizza 52, Torino 10126, Italy
| | - Myriam Foglietta
- Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Via Nizza 52, Torino 10126, Italy.,Centro di Ricerca in Medicina Sperimentale (CeRMS), AOU Città della Salute e della Scienza di Torino, Via Santena 5, Torino 10126, Italy
| | - Nico Mitro
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, Milano 20133, Italy
| | - Donatella Caruso
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, Milano 20133, Italy
| | - Francesco Novelli
- Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Via Nizza 52, Torino 10126, Italy.,Centro Interdipartimentale di Ricerca per le Biotecnologie Molecolari (CIRBM), Via Nizza 52, Torino 10126, Italy
| | - Chiara Riganti
- Centro di Ricerca in Medicina Sperimentale (CeRMS), AOU Città della Salute e della Scienza di Torino, Via Santena 5, Torino 10126, Italy.,Dipartimento di Oncologia, Università degli Studi di Torino, Via Santena 5/bis, Torino 10126, Italy
| | - Massimo Massaia
- Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Via Nizza 52, Torino 10126, Italy.,Centro di Ricerca in Medicina Sperimentale (CeRMS), AOU Città della Salute e della Scienza di Torino, Via Santena 5, Torino 10126, Italy.,Centro Interdipartimentale di Ricerca per le Biotecnologie Molecolari (CIRBM), Via Nizza 52, Torino 10126, Italy.,SC. Ematologia, AO S. Croce e Carle, Via Michele Coppino 26, Cuneo 12100, Italy
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Rhee EJ, Byrne CD, Sung KC. The HDL cholesterol/apolipoprotein A-I ratio: an indicator of cardiovascular disease. Curr Opin Endocrinol Diabetes Obes 2017; 24:148-153. [PMID: 28099205 DOI: 10.1097/med.0000000000000315] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
PURPOSE OF REVIEW In multiple studies, the HDL cholesterol (HDL-C) concentration has been shown to be inversely associated with cardiovascular disease (CVD) and CVD risk. Based on this observation, increasing the plasma HDL-C concentration is thought to be a desirable strategy, in the 21st century, for decreasing the burden of CVD. RECENT FINDINGS Recent studies have shown that powerful HDL-C concentration-increasing drugs are ineffective for decreasing CVD. Increasing evidence now shows that HDL is an unstable and heterogeneous particle, and that 'HDL particle functionality' is far more important in atheroprotection than is the HDL-C level, alone. Apolipoprotein A-I (apoA-I) is the major protein component of HDL, and increasing evidence suggests that the ratio of HDL-C to apoA-I may give additional insight as a risk marker not just for CVD but also for all-cause and cancer mortality. SUMMARY In this review, we discuss the importance of HDL composition, apoA-I levels, and the HDL-C/apoA-I ratio for predicting CVD and mortality outcomes.
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Affiliation(s)
- Eun-Jung Rhee
- aDivision of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea bEndocrinology and Metabolism Unit, Southampton General Hospital, University of Southampton, Southampton, UK cDivision of Cardiology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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37
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Choi HY, Hafiane A, Schwertani A, Genest J. High-Density Lipoproteins: Biology, Epidemiology, and Clinical Management. Can J Cardiol 2017; 33:325-333. [DOI: 10.1016/j.cjca.2016.09.012] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Revised: 09/18/2016] [Accepted: 09/19/2016] [Indexed: 01/29/2023] Open
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Li J, Wang W, Han L, Feng M, Lu H, Yang L, Hu X, Shi S, Jiang S, Wang Q, Ye L. Human apolipoprotein A-I exerts a prophylactic effect on high-fat diet-induced atherosclerosis via inflammation inhibition in a rabbit model. Acta Biochim Biophys Sin (Shanghai) 2017; 49:149-158. [PMID: 28069582 DOI: 10.1093/abbs/gmw128] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 11/29/2016] [Indexed: 01/15/2023] Open
Abstract
Apolipoprotein A-I (apoA-I) is the major functional protein fraction of high-density lipoprotein. The prophylactic effect and mechanism of human apoA-I on atherosclerosis (AS) were investigated in a high-fat diet-induced AS rabbit model. The rabbits were injected with apoA-I once a week while fed high-fat diet for 20 weeks. Our results showed that apoA-I could raise the serum level of high-density lipoprotein-cholesterol and reduce those of lipid total cholesterol, triglyceride, and low-density lipoprotein-cholesterol in AS rabbits. Decreased aortic plaque area and aortic injury degree were also observed by Oil Red O staining and HE staining in apoA-I-treated high-fat diet-induced AS rabbits. Further study elucidated that apoA-I could down-regulate the expression of some inflammatory mediators including intercellular adhesion molecule type 1, vascular adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1, tumor necrosis factor-α, interleukin-6 (IL-6), and C-reactive protein in serum and aorta of AS rabbits. In addition, real-time quantitative RT-PCR analyses showed that the apoA-I infusions decreased the mRNA levels of two pro-inflammatory molecules, i.e. nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (COX-2), in aorta of AS rabbits, which was associated with a concomitant reduction in endothelial VCAM-1 and IL-6 mRNA transcription. Together, our results support the atheroprotective and prophylactic role of apoA-I in vivo, and this activity may be correlated with its anti-inflammatory effect.
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Affiliation(s)
- Jiyang Li
- Department of Biosynthesis & Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Weina Wang
- Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Lei Han
- Shanghai Benemae Pharmaceutical Corporation, Shanghai International Medical Park, Shanghai 201321, China
| | - Meiqing Feng
- Department of Biosynthesis & Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Hui Lu
- Shanghai RAAS Blood Products Co., Ltd, Shanghai 201401, China
| | - Li Yang
- Shanghai RAAS Blood Products Co., Ltd, Shanghai 201401, China
| | - Xiangxiang Hu
- Department of Biosynthesis & Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Si Shi
- Department of Biosynthesis & Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Shanshan Jiang
- Department of Biosynthesis & Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Qian Wang
- Department of Biosynthesis & Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Li Ye
- Department of Biosynthesis & Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
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Apolipoprotein A-I Mimetic Peptide D-4F Reduces Cardiac Hypertrophy and Improves Apolipoprotein A-I–Mediated Reverse Cholesterol Transport From Cardiac Tissue in LDL Receptor-null Mice Fed a Western Diet. J Cardiovasc Pharmacol 2016; 67:412-7. [DOI: 10.1097/fjc.0000000000000365] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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40
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Gilham D, Wasiak S, Tsujikawa LM, Halliday C, Norek K, Patel RG, Kulikowski E, Johansson J, Sweeney M, Wong NCW, Gordon A, McLure K, Young P. RVX-208, a BET-inhibitor for treating atherosclerotic cardiovascular disease, raises ApoA-I/HDL and represses pathways that contribute to cardiovascular disease. Atherosclerosis 2016; 247:48-57. [PMID: 26868508 DOI: 10.1016/j.atherosclerosis.2016.01.036] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 01/20/2016] [Accepted: 01/21/2016] [Indexed: 12/18/2022]
Abstract
High density lipoproteins (HDL), through activity of the main protein component apolipoprotein A-I (ApoA-I), can reduce the risk of cardiovascular disease (CVD) by removing excess cholesterol from atherosclerotic plaque. In this study, we demonstrate that the bromodomain and extraterminal domain (BET) inhibitor RVX-208 increases ApoA-I gene transcription and protein production in human and primate primary hepatocytes. Accordingly, RVX-208 also significantly increases levels of ApoA-I, HDL-associated cholesterol, and HDL particle number in patients who received the compound in recently completed phase 2b trials SUSTAIN and ASSURE. Moreover, a post-hoc analysis showed lower instances of major adverse cardiac events in patients receiving RVX-208. To understand the effects of RVX-208 on biological processes underlying cardiovascular risk, we performed microarray analyses of human primary hepatocytes and whole blood treated ex vivo. Overall, data showed that RVX-208 raises ApoA-I/HDL and represses pro-inflammatory, pro-atherosclerotic and pro-thrombotic pathways that can contribute to CVD risk.
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41
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Lee MKS, Moore XL, Fu Y, Al-Sharea A, Dragoljevic D, Fernandez-Rojo MA, Parton R, Sviridov D, Murphy AJ, Chin-Dusting JPF. High-density lipoprotein inhibits human M1 macrophage polarization through redistribution of caveolin-1. Br J Pharmacol 2015; 173:741-51. [PMID: 26332942 DOI: 10.1111/bph.13319] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 08/19/2015] [Accepted: 08/25/2015] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND PURPOSE Monocyte-derived macrophages are critical in the development of atherosclerosis and can adopt a wide range of functional phenotypes depending on their surrounding milieu. High-density lipoproteins (HDLs) have many cardio-protective properties including potent anti-inflammatory effects. We investigated the effects of HDL on human macrophage phenotype and the mechanisms by which these occur. EXPERIMENTAL APPROACH Human blood monocytes were differentiated into macrophages in the presence or absence of HDL and were then induced to either an inflammatory macrophage (M1) or anti-inflammatory macrophage (M2) phenotype using LPS and IFN-γ or IL-4, respectively. KEY RESULTS HDL inhibited the induction of macrophages to an M1-phenotype, as evidenced by a decrease in the expression of M1-specific cell surface markers CD192 and CD64, as well as M1-associated inflammatory genes TNF-α, IL-6 and MCP-1 (CCL2). HDL also inhibited M1 function by reducing the production of ROS. In contrast, HDL had no effect on macrophage induction to the M2-phenotype. Similarly, methyl-β-cyclodextrin, a non-specific cholesterol acceptor also suppressed the induction of M1 suggesting that cholesterol efflux is important in this process. Furthermore, HDL decreased membrane caveolin-1 in M1 macrophages. We confirmed that caveolin-1 is required for HDL to inhibit M1 induction as bone marrow-derived macrophages from caveolin-1 knockout mice continued to polarize into M1-phenotype despite the presence of HDL. Moreover, HDL decreased ERK1/2 and STAT3 phosphorylation in M1 macrophages. CONCLUSIONS AND IMPLICATIONS We concluded that HDL reduces the induction of macrophages to the inflammatory M1-phenotype via redistribution of caveolin-1, preventing the activation of ERK1/2 and STAT3.
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Affiliation(s)
- Man K S Lee
- Baker IDI Heart and Diabetes Institute, Melbourne, Australia.,Department of Medicine (Alfred), Monash University, Melbourne, Australia
| | - Xiao-Lei Moore
- Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Yi Fu
- Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Annas Al-Sharea
- Baker IDI Heart and Diabetes Institute, Melbourne, Australia.,Department of Medicine (Alfred), Monash University, Melbourne, Australia
| | - Dragana Dragoljevic
- Baker IDI Heart and Diabetes Institute, Melbourne, Australia.,Department of Medicine (Alfred), Monash University, Melbourne, Australia
| | - Manuel A Fernandez-Rojo
- Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Robert Parton
- Institute for Molecular Bioscience and Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane, Australia
| | - Dmitri Sviridov
- Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Andrew J Murphy
- Baker IDI Heart and Diabetes Institute, Melbourne, Australia.,Department of Immunology, Monash University, Melbourne, Australia
| | - Jaye P F Chin-Dusting
- Baker IDI Heart and Diabetes Institute, Melbourne, Australia.,Department of Medicine (Alfred), Monash University, Melbourne, Australia
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Hafiane A, Bielicki JK, Johansson JO, Genest J. Novel Apo E-Derived ABCA1 Agonist Peptide (CS-6253) Promotes Reverse Cholesterol Transport and Induces Formation of preβ-1 HDL In Vitro. PLoS One 2015. [PMID: 26207756 PMCID: PMC4514675 DOI: 10.1371/journal.pone.0131997] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Apolipoprotein (apo) mimetic peptides replicate some aspects of HDL function. We have previously reported the effects of compound ATI-5261 on its ability to replicate many functions of native apo A-I in the process of HDL biogenesis. ATI-5261 induced muscle toxicity in wild type C57Bl/6 mice, increased CPK, ALT and AST and increase in triglyceride (Tg) levels. Aromatic phenylalanine residues on the non-polar face of ATI-5261, together with positively charged arginine residues at the lipid-water interface were responsible for these effects. This information was used to create a novel analog (CS-6253) that was non-toxic. We evaluated this peptide designed from the carboxyl terminus of apo E, in its ability to mimic apo A-I functionality. Our data shows that the lipidated particles generated by incubating cells overexpressing ABCA1 with lipid free CS-6253 enhances the rate of ABCA1 lipid efflux with high affinity interactions with native ABCA1 oligomeric forms and plasma membrane micro-domains. Interaction between ABCA1 and lipid free CS-6253 resulted in formation of nascent HDL-CS-6253 particles that are actively remodeled in plasma. Mature HDL-CS-6253 particles deliver cholesterol to liver cells via SR-BI in-vitro. CS-6253 significantly increases cholesterol efflux in murine macrophages and in human THP-1 macrophage-derived foam cells expressing ABCA1. Addition of CS-6253 to plasma dose-dependently displaced apo A-I from α-HDL particles and led to de novo formation of preβ-1 HDL that stimulates ABCA1 dependent cholesterol efflux efficiently. When incubated with human plasma CS-6253 was also found to bind with HDL and LDL and promoted the transfer of cholesterol from HDL to LDL predominantly. Our data shows that CS-6253 mimics apo A-I in its ability to promote ABCA1-mediated formation of nascent HDL particles, and enhances formation of preβ-1 HDL with increase in the cycling of apo A-I between the preβ and α-HDL particles in-vitro. These mechanisms are potentially anti-atherogenic.
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Affiliation(s)
- Anouar Hafiane
- Cardiovascular Research Laboratories Laboratory, Research Institute of the McGill University Health Centre, Montréal, Québec H4A 3J1, Canada
| | - John K. Bielicki
- Lawrence Berkeley National Laboratory, Donner Laboratory, MS1-267, Berkeley, CA, United States of America
| | | | - Jacques Genest
- Cardiovascular Research Laboratories Laboratory, Research Institute of the McGill University Health Centre, Montréal, Québec H4A 3J1, Canada
- * E-mail:
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Graham A, Allen AM. Mitochondrial function and regulation of macrophage sterol metabolism and inflammatory responses. World J Cardiol 2015; 7:277-286. [PMID: 26015858 PMCID: PMC4438467 DOI: 10.4330/wjc.v7.i5.277] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Revised: 02/25/2015] [Accepted: 03/18/2015] [Indexed: 02/06/2023] Open
Abstract
The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis. Macrophage generation of oxysterol activators of liver X receptors (LXRs), via sterol 27-hydroxylase, is regulated by the rate of flux of cholesterol to the inner mitochondrial membrane, via a complex of cholesterol trafficking proteins. Oxysterols are key signalling molecules, regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production, key features influencing the impact of these cells within atherosclerotic lesions. The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate, but may include steroidogenic acute regulatory protein and translocator protein. There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters (ABCA1, ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages. Thus, molecules which can sustain or improve mitochondrial structure, the function of the electron transport chain, or increase the activity of components of the protein complex involved in cholesterol transfer, may therefore have utility in limiting or regressing atheroma development, reducing the incidence of coronary heart disease and myocardial infarction.
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44
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Swerdlow DI, Hingorani AD, Humphries SE. Genetic Risk Factors and Mendelian Randomization in Cardiovascular Disease. Curr Cardiol Rep 2015; 17:33. [DOI: 10.1007/s11886-015-0584-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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45
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Park SH, Paek JH, Shin D, Lee JY, Lim SS, Kang YH. Purple perilla extracts with α-asarone enhance cholesterol efflux from oxidized LDL-exposed macrophages. Int J Mol Med 2015; 35:957-65. [PMID: 25673178 PMCID: PMC4356441 DOI: 10.3892/ijmm.2015.2101] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 02/02/2015] [Indexed: 12/12/2022] Open
Abstract
The cellular accumulation of cholesterol is critical in the development and progression of atherosclerosis. ATP-binding cassette (ABC) transporters play an essential role in mediating the efflux of excess cholesterol. In the current study, we investigated whether purple Perilla frutescens extracts (PPE) at a non-toxic concentration of 1-10 µg/ml stimulate the induction of the ABC transporters, ABCA1 and ABCG1, and cholesterol efflux from lipid-laden J774A.1 murine macrophages exposed to 50 ng/ml oxidized low-density lipoprotein (LDL). Purple perilla, an annual herb in the mint family and its constituents, have been reported to exhibit antioxidant and cytostatic activity, as well as to exert anti-allergic effects. Our results revealed that treatment with oxidized LDL for 24 h led to the accumulation of lipid droplets in the macrophages. PPE suppressed the oxidized LDL-induced foam cell formation by blocking the induction of scavenger receptor B1. However, PPE promoted the induction of the ABC transporters, ABCA1 and ABCG1, and subsequently accelerated cholesterol efflux from the lipid-loaded macrophages. The liver X receptor (LXR) agonist, TO-091317, and the peroxisome proliferator-activated receptor (PPAR) agonist, pioglitazone, increased ABCA1 expression and treatment with 10 µg/ml PPE further enhanced this effect. PPE did not induce LXRα and PPARγ expression per se, but enhanced their expression in the macrophages exposed to oxidized LDL. α-asarone was isolated from PPE and characterized as a major component enhancing the induction of ABCA1 and ABCG1 in macrophages exposed to oxidized LDL. α-asarone, but not β-asarone was effective in attenuating foam cell formation and enhancing cholesterol efflux, revealing an isomeric difference in their activity. The results from the present study demonstrate that PPE promotes cholesterol efflux from macrophages by activating the interaction of PPARγ-LXRα-ABC transporters.
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Affiliation(s)
- Sin-Hye Park
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Kangwon-do 200-702, Republic of Korea
| | - Ji Hun Paek
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Kangwon-do 200-702, Republic of Korea
| | - Daekeun Shin
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Kangwon-do 200-702, Republic of Korea
| | - Jae-Yong Lee
- Department of Biochemistry, School of Medicine, Hallym University, Chuncheon, Kangwon-do 200-702, Republic of Korea
| | - Soon Sung Lim
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Kangwon-do 200-702, Republic of Korea
| | - Young-Hee Kang
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Kangwon-do 200-702, Republic of Korea
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46
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Hafiane A, Genest J. High density lipoproteins: Measurement techniques and potential biomarkers of cardiovascular risk. BBA CLINICAL 2015; 3:175-88. [PMID: 26674734 PMCID: PMC4661556 DOI: 10.1016/j.bbacli.2015.01.005] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2014] [Revised: 01/16/2015] [Accepted: 01/26/2015] [Indexed: 12/31/2022]
Abstract
Plasma high density lipoprotein cholesterol (HDL) comprises a heterogeneous family of lipoprotein species, differing in surface charge, size and lipid and protein compositions. While HDL cholesterol (C) mass is a strong, graded and coherent biomarker of cardiovascular risk, genetic and clinical trial data suggest that the simple measurement of HDL-C may not be causal in preventing atherosclerosis nor reflect HDL functionality. Indeed, the measurement of HDL-C may be a biomarker of cardiovascular health. To assess the issue of HDL function as a potential therapeutic target, robust and simple analytical methods are required. The complex pleiotropic effects of HDL make the development of a single measurement challenging. Development of laboratory assays that accurately HDL function must be developed validated and brought to high-throughput for clinical purposes. This review discusses the limitations of current laboratory technologies for methods that separate and quantify HDL and potential application to predict CVD, with an emphasis on emergent approaches as potential biomarkers in clinical practice.
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Key Words
- 2D-PAGGE, two dimensional polyacrylamide gradient gel electrophoresis
- ApoA-I, apolipoprotein A-I
- Apolipoprotein A-I
- Atherosclerosis
- Biomarkers of cardiovascular risk
- CHD, coronary heart disease
- CVD, cardiovascular disease
- Cellular cholesterol efflux
- Coronary artery disease
- HDL, high density lipoprotein
- HPLC, High Performance Liquid Chromatography
- High density lipoproteins
- LCAT, lecithin–cholesterol acyltransferase
- LDL, low density lipoprotein
- MALDI, matrix-assisted laser desorption/ionization
- MOP, myeloperoxidase
- MS/MS, tandem-mass spectrometry
- ND-PAGGE, non-denaturant polyacrylamide gradient gel electrophoresis
- NMR, nuclear magnetic resonance
- PEG, polyethylene glycol
- PON1, paraoxonase 1
- SELDI, surface enhanced laser desorption/ionization
- TOF, time-of-flight
- UTC, ultracentrifugation
- Vascular endothelial function
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Affiliation(s)
- Anouar Hafiane
- McGill University Health Center, Royal Victoria Hospital, 687 Avenue des Pins West, Montreal, QC H3A 1A1, Canada
| | - Jacques Genest
- McGill University Health Center, Royal Victoria Hospital, 687 Avenue des Pins West, Montreal, QC H3A 1A1, Canada
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Gugliucci A, Menini T. Paraoxonase 1 and HDL maturation. Clin Chim Acta 2014; 439:5-13. [PMID: 25261854 DOI: 10.1016/j.cca.2014.09.016] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 09/16/2014] [Accepted: 09/19/2014] [Indexed: 01/25/2023]
Abstract
Understanding the kinetics and function of paraoxonase 1 (PON1) is becoming an important issue in atherosclerosis. Low PON1 activity has been consistently linked with an increased risk of major cardiovascular events in the setting of secondary prevention of coronary artery disease. Recent studies have shown that there is a specific interaction of myeloperoxidase (MPO)-apoAI-PON1 on HDL surface that seems to be germane to atherogenesis. MPO specifically inhibits PON1 and PON1 mitigates MPO effects. Surprisingly, very little is known about the routes by which PON1 gets integrated into HDL or its fate during HDL remodeling in the intravascular space. We have developed a method that assesses PON1 activity in the individual HDL subclasses with the aid of which we have shown that PON1 is present across the HDL particle range and preferentially in HDL3, confirming data from ultracentrifugation (UC) studies. Upon HDL maturation ex vivo PON1 is activated and it shows a flux to both smaller and larger HDL particles as well as to VLDL and sdLDL. At the same time apoE, AI and AII are shifted across particle sizes. PON1 activation and flux across HDL particles are blocked by CETP and LCAT inhibitors. In a group of particles with such a complex biology as HDL, knowledge of the interaction between apo-lipoproteins, lipids and enzymes is key for an increased understanding of the yet multiple unknown features of its function. Solving the HDL paradox will necessitate the development of techniques to explore HDL function that are practical and well adapted to clinical studies and eventually become useful in patient monitoring. The confluence of proteomic, functional studies, HDL subclasses, PON1 assays and zymogram will yield data to draw a more elaborate and comprehensive picture of the function of HDL. It must be noted that all these studies are static and conducted in the fasting state. The crucial phase will be achieved when human kinetic studies (both in the fasting and post-prandial states) on HDL-PON1, apoA-I and lipid fate in the circulation are carried out.
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Affiliation(s)
- Alejandro Gugliucci
- Glycation, Oxidation and Disease Laboratory, Touro University California College of Osteopathic Medicine, Vallejo, CA, USA.
| | - Teresita Menini
- Glycation, Oxidation and Disease Laboratory, Touro University California College of Osteopathic Medicine, Vallejo, CA, USA
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Yilmaz H, Bozkurt A, Cakmak M, Celik HT, Bilgic MA, Bavbek N, Akcay A. Relationship between late arteriovenous fistula (AVF) stenosis and neutrophil–lymphocyte ratio (NLR) in chronic hemodialysis patients. Ren Fail 2014; 36:1390-4. [DOI: 10.3109/0886022x.2014.945183] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
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RISK and SAFE signaling pathway involvement in apolipoprotein A-I-induced cardioprotection. PLoS One 2014; 9:e107950. [PMID: 25237809 PMCID: PMC4169577 DOI: 10.1371/journal.pone.0107950] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 08/18/2014] [Indexed: 01/24/2023] Open
Abstract
Recent findings indicate that apolipoprotein A-I (ApoA-I) may be a protective humoral mediator involved in remote ischemic preconditioning (RIPC). This study sought to determine if ApoA-I mediates its protective effects via the RISK and SAFE signaling pathways implicated in RIPC. Wistar rats were allocated to one of the following groups. Control: rats were subjected to myocardial ischemia/reperfusion (I/R) without any further intervention; RIPC: four cycles of limb I/R were applied prior to myocardial ischemia; ApoA-I: 10 mg/Kg of ApoA-I were intravenously injected prior to myocardial ischemia; ApoA-I + inhibitor: pharmacological inhibitors of RISK/SAFE pro-survival kinase (Akt, ERK1/2 and STAT-3) were administered prior to ApoA-I injection. Infarct size was significantly reduced in the RIPC group compared to Control. Similarly, ApoA-I injection efficiently protected the heart, recapitulating RIPC-induced cardioprotection. The ApoA-I protective effect was associated with Akt and GSK-3β phosphorylation and substantially inhibited by pretreatment with Akt and ERK1/2 inhibitors. Pretreatment with ApoA-I in a rat model of I/R recapitulates RIPC-induced cardioprotection and shares some similar molecular mechanisms with those of RIPC-involved protection of the heart.
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Kingwell BA, Chapman MJ, Kontush A, Miller NE. HDL-targeted therapies: progress, failures and future. Nat Rev Drug Discov 2014; 13:445-64. [DOI: 10.1038/nrd4279] [Citation(s) in RCA: 256] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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