Cardiovascular protective effects of GLP-1: a focus on the MAPK signaling pathway.

Cardiovascular and related metabolic diseases are significant global health challenges. Glucagon-like peptide 1 (GLP-1) is a brain-gut peptide secreted by the ileal endocrine system and is now an established drug target in type 2 diabetes (T2DM). GLP-1 targeting agents have been shown not only to treat T2DM, but also to exert cardiovascular protective effects by regulating multiple signaling pathways. The mitogen-activated protein kinase (MAPK) pathway, a common signal transduction pathway for transmitting extracellular signals to downstream effector molecules, is involved in regulating diverse cellular physiological processes, including cell proliferation, differentiation, stress, inflammation, functional synchronization, transformation, and apoptosis. The purpose of this review is to highlight the relationship between GLP-1 and cardiovascular disease (CVD) and discuss how GLP-1 exerts cardiovascular protective effects through the MAPK signaling pathway. This review also discusses the future challenges in fully characterizing and evaluating the CVD protective effects of GLP-1 receptor agonists (GLP-1RA) at the cellular and molecular levels. A better understanding of the MAPK signaling pathway that is dysregulated in CVD may aid in the design and development of promising GLP-1RA.

Regulating the Warburg effect on metabolic stress and myocardial fibrosis remodeling and atrial intracardiac waveform activity induced by atrial fibrillation.

Atrial fibrillation (AF) is associated with metabolic stress and induces myocardial fibrosis reconstruction by increasing glycolysis. One goal in the treatment of paroxysmal AF (p-AF) is to improve myocardial fibrosis reconstruction and myocardial metabolic stress caused by the Warburg effect. Adopted male canine that rapid right atrial pacing (RAP) for 6 days to establish a p-AF model. The canines were pre-treated with phenylephrine (PE) or dichloroacetic acid (DCA) before exposure to p-AF or non-p-AF. P-wave duration (Pmax), minimum P-wave duration (Pmin), P wave dispersion (PWD), atrial effective refractory period (AERP) and AERP dispersion (AERPd) were measured in canine atrial cardiomyocytes. Pyruvate dehydrogenase kinase-1 (PDK-1), PDK-4, lactate dehydrogenase A (LDHA), pyruvate dehydrogenase (PDH), citrate synthase (CS), isocitrate dehydrogenase (IDH), and matrix metalloproteinase 9 (MMP-9) were evaluated by western blotting and reverse transcription polymerase chain reaction (RT-PCR), content of adenosine monophosphate (AMP), adenosine triphosphate (ATP), lactic acid and glycogen, and activity of LDHA, PDK-1 and PDK-4 were evaluated by enzyme-linked immunosorbent assay (ELISA), myocardial tissue glycogen content was evaluated by PAS, myocardial fibrosis remodeling was evaluated by hematoxylin and eosin (H&E) and Masson staining. Our findings demonstrated that p-AF increases the Warburg effect-related metabolic stress and myocardial fibrosis remodeling by increasing the expression and activity of PDK-1, PDK-4, and LDHA, content of AMP and lactic acid, and the ratio of AMP/ATP and decreasing the expression of PDH, CS, and IDH, and glycogen content. In addition, p-AF can induce cardiomyocyte fibrosis remodeling and increase MMP-9 expression, and p-AF also increases atrial intracardiac waveform activity by prolonging Pmax, Pmin, PWD, and AERPd and shortening AERP. PDK isoforms agonists (PE) produce a similar p-AF pathological effect and can produce synergistic effects with p-AF, further increasing Warburg effect-related metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity. In contrast, the use of PDK-specific inhibitors (DCA) completely reverses these pathophysiological changes induced by p-AF. We demonstrate that p-AF can induce the Warburg effect in canine atrial cardiomyocytes and significantly improve p-AF-induced metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity by inhibiting the Warburg effect.

Perivascular adipose tissue (PVAT) in atherosclerosis: a double-edged sword.

Perivascular adipose tissue (PVAT), the adipose tissue that surrounds most of the vasculature, has emerged as an active component of the blood vessel wall regulating vascular homeostasis and affecting the pathogenesis of atherosclerosis. Although PVAT characteristics resemble both brown and white adipose tissues, recent evidence suggests that PVAT develops from its own distinct precursors implying a closer link between PVAT and vascular system. Under physiological conditions, PVAT has potent anti-atherogenic properties mediated by its ability to secrete various biologically active factors that induce non-shivering thermogenesis and metabolize fatty acids. In contrast, under pathological conditions (mainly obesity), PVAT becomes dysfunctional, loses its thermogenic capacity and secretes pro-inflammatory adipokines that induce endothelial dysfunction and infiltration of inflammatory cells, promoting atherosclerosis development. Since PVAT plays crucial roles in regulating key steps of atherosclerosis development, it may constitute a novel therapeutic target for the prevention and treatment of atherosclerosis. Here, we review the current literature regarding the roles of PVAT in the pathogenesis of atherosclerosis.

PI3K/Akt/FoxO3a signaling mediates cardioprotection of FGF-2 against hydrogen peroxide-induced apoptosis in H9c2 cells.

Cardiovascular disease is a growing major global public health problem. Oxidative stress is regarded as one of the key regulators of pathological physiology, which eventually leads to cardiovascular disease. However, mechanisms by which FGF-2 rescues cells from oxidative stress damage in cardiovascular disease is not fully elucidated. Herein this study was designed to investigate the protective effects of FGF-2 in H2O2-induced apoptosis of H9c2 cardiomyocytes, as well as the possible signaling pathway involved. Apoptosis of H9c2 cardiomyocytes was induced by H2O2 and assessed using methyl thiazolyl tetrazolium assay, Hoechst, and TUNEL staining. Cells were pretreated with PI3K/Akt inhibitor LY294002 to investigate the possible PI3K/Akt pathways involved in the protection of FGF-2. The levels of p-Akt, p-FoxO3a, and Bim were detected by immunoblotting. Stimulation with H2O2 decreased the phosphorylation of Akt and FoxO3a, and induced nuclear localization of FoxO3a and apoptosis of H9c2 cells. These effects of H2O2 were abrogated by pretreatment with FGF-2. Furthermore, the protective effects of FGF-2 were abolished by PI3K/Akt inhibitor LY294002. In conclusion, our data suggest that FGF-2 protects against H2O2-induced apoptosis of H9c2 cardiomyocytes via activation of the PI3K/Akt/FoxO3a pathway.

Mipu1 inhibits lipid accumulation through down-regulation of CD36 in RAW264.7 cells.

BACKGROUND/AIMS: Our recent data indicated that Mipu1 overexpression reduces lipid intake and CD36 expression of macrophages in the presence of oxLDL. However, the mechanism of Mipu1 inhibiting lipid accumulation in macrophages is not elucidated. METHODS: Real-time quantitative polymerase chain reaction (PCR) and western blot analysis were used to detect expression of Mipu1 and CD36. The promoter activity of CD36 was studied using luciferase assays. Chromatin immunoprecipitation (ChIP) was used to show the recruitment of Mipu1 onto the CD36 promoter. High-performance liquid chromatography and Dil-labeled lipoprotein were used to detect cholesterol accumulation. RESULTS: Here, we show that CD36 overexpression rescues oxLDL-induced cholesterol accumulation in RAW264.7-Mipu1 cells. Analysis of the mouse CD36 promoter revealed two potential Mipu1-response elements (MRE), one of which (from -237bp to -244bp, ACTTAC) was shown, using mutagenesis and deletion analysis, to be functional. Mipu1 was demonstrated to bind to CD36 promoter, and oxLDL treatment resulted in increases in their interaction as assessed by ChIP. CONCLUSIONS: It was demonstrated that Mipu1 inhibited the lipid accumulation of macrophages and it down-regulated CD36 expression in the presence of oxLDL.

ZNF667 Suppressed LPS-induced Macrophages Inflammation through mTOR-dependent Aerobic Glycolysis Regulation.

BACKGROUND: Macrophages participate in all stages of the inflammatory response, and the excessive release of inflammatory mediators and other cytokines synthesized and secreted by macrophages is fundamentally linked to an uncontrolled inflammatory response. The zinc finger 667 (ZNF667) protein, a novel DNAbinding protein, has been shown to play a vital role in oxidative stress. However, none of the target genes in macrophages or the potential roles of ZNF667 have been elucidated to date. > Objectives: The present study was designed to investigate the effects of ZNF667 on LPS-induced inflammation in macrophages. > Methods: The RAW264.7 macrophage cell line was selected as a model system. Inflammatory response-related gene expression levels and phosphorylation levels of PI3K, AKT, and mTOR were detected in LPS-treated macrophages via RT-PCR and western blotting, respectively. > Results: We found that LPS resulted in the up-regulation of ZNF667 in macrophages and a peak response in ZNF667 protein expression levels when used at a concentration of 100 ng/mL. ZNF667 overexpression significantly inhibited the LPS-induced up-regulation of iNOS, and IL-1ß mRNA and protein expression levels, together with the secretion of IL-1ß, IL-6, and TNF-α. ZNF667 overexpression also inhibited PI3K, AKT, and mTOR hyperphosphorylation and had no effect on the phosphorylation of NF-κB p65, ERK1/2, MAPK p38, and the transcriptional activity of NF-κB in macrophages. The up-regulation of ZNF667 inhibited the levels of expression of HK2 and PFKFB3, glucose consumption, and lactate production in LPS-stimulated macrophages. The up-regulation of mRNA levels of LPS-induced glycolytic genes HK2 and PFKFB3 and the increased mRNA expression of pro-inflammatory cytokines (IL-1ß and iNOS) were abolished by hexokinase inhibitor 2-DG in ZNF667-deficient macrophages. Meanwhile, glucose consumption and lactate production were abrogated in macrophages when cells were treated with the specific mTOR inhibitor RPM. > Conclusion: Our results demonstrate that ZNF667 suppressed LPS-stimulated RAW264.7 macrophage inflammation by regulating mTOR-dependent aerobic glycolysis.>.

Hydrogen sulfide improves ox­LDL­induced expression levels of Lp­PLA2 in THP­1 monocytes via the p38MAPK pathway.

Hydrogen sulfide (H2S) exerts an anti­atherosclerotic effect and decreases foam cell formation. Lipoprotein­associated phospholipase A2 (Lp­PLA2) is a key factor involved in foam cell formation. However, the association between H2S and Lp­PLA2 expression levels with respect to foam cell formation has not yet been elucidated. The present study investigated whether H2S can affect foam cell formation and potential signalling pathways via regulation of the expression and activity of Lp­PLA2. Using human monocytic THP­1 cells as a model system, it was observed that oxidized low­density lipoprotein (ox­LDL) not only upregulates the expression level and activity of Lp­PLA2, it also downregulates the expression level and activity of Cystathionine γ lyase. Exogenous supplementation of H2S decreased the expression and activity of Lp­PLA2 induced by ox­LDL. Moreover, ox­LDL induced the expression level and activity of Lp­PLA2 via activation of the p38MAPK signalling pathway. H2S blocked the expression levels and activity of Lp­PLA2 induced by ox­LDL via inhibition of the p38MAPK signalling pathway. Furthermore, H2S inhibited Lp­PLA2 activity by blocking the p38MAPK signaling pathway and significantly decreased lipid accumulation in ox­LDL­induced macrophages, as detected by Oil Red O staining. The results of the present study indicated that H2S inhibited ox­LDL­induced Lp­PLA2 expression levels and activity by blocking the p38MAPK signalling pathway, thereby improving foam cell formation. These findings may provide novel insights into the role of H2S intervention in the progression of atherosclerosis.

Oxidative stress in vascular calcification.

Vascular calcification (VC), which is closely associated with significant mortality in cardiovascular disease, chronic kidney disease (CKD), and/or diabetes mellitus, is characterized by abnormal deposits of hydroxyapatite minerals in the arterial wall. The impact of oxidative stress (OS) on the onset and progression of VC has not been well described. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidases, myeloperoxidase (MPO), nitric oxide synthases (NOSs), superoxide dismutase (SOD) and paraoxonases (PONs) are relevant factors that influence the production of reactive oxygen species (ROS). Furthermore, excess ROS-induced OS has emerged as a critical mediator promoting VC through several mechanisms, including phosphate balance, differentiation of vascular smooth muscle cells (VSMCs), inflammation, DNA damage, and extracellular matrix remodeling. Because OS is a significant regulator of VC, antioxidants may be considered as novel treatment options.

Adipokines in vascular calcification.

Adipose tissue (AT), a critical endocrine gland, is capable of producing and secreting abundant adipokines. Adipokines act on distant or adjacent organ tissues via paracrine, autocrine, and endocrine mechanism, which play attractive roles in the regulation of glycolipid metabolism and inflammatory response. Increasing evidence shows that adipokines can connect obesity with cardiovascular diseases by serving as promoters or inhibitors in vascular calcification. The chronic hypoxia in AT, caused by the adipocyte hypertrophy, is able to trigger imbalanced adipokine generation, which leads to apoptosis, osteogenic differentiation of vascular smooth muscle cells (VSMCs), vascular inflammation, and abnormal deposition of calcium and phosphorus in the vessel wall. The objectives of this review aim at providing a brief summary of the crucial influence of major adipokines on the formation and development of vascular calcification, which may contribute to better understanding these adipokines for establishing the appropriate therapeutic strategies to counteract obesity-associated vascular calcification.

Role of Kruppel-like factor 4 in atherosclerosis.

Atherosclerosis is one of the chronic progressive diseases, which is caused by vascular injury and promoted by the interaction of various inflammatory factors and inflammatory cells. In recent years, kruppel-like factor 4 (KLF4), a significant transcription factor that participated in cell growth, differentiation and proliferation, has been proved to cause substantial impacts on regulating cardiovascular disease. This paper will give a comprehensive summary to highlight KLF4 as a crucial regulator of foam cell formation, vascular smooth muscle cells (VSMCs) phenotypic transformation, macrophage polarization, endothelial cells inflammation, lymphocyte differentiation and cell proliferation in the process of atherosclerosis. Recent studies show that KLF4 may be an important "molecular switch" in the process of improving vascular injury and inflammation under harmful stimulation, suggesting that KLF4 is a latent disease biomarker for the therapeutic target of atherosclerosis and vascular disease.

Hydrogen Sulfide Ameliorates Angiotensin II-Induced Atrial Fibrosis Progression to Atrial Fibrillation Through Inhibition of the Warburg Effect and Endoplasmic Reticulum Stress.

Atrial fibrosis is the basis for the occurrence and development of atrial fibrillation (AF) and is closely related to the Warburg effect, endoplasmic reticulum stress (ERS) and mitochondrion dysfunctions-induced cardiomyocyte apoptosis. Hydrogen sulfide (H2S) is a gaseous signalling molecule with cardioprotective, anti-myocardial fibrosis and improved energy metabolism effects. Nevertheless, the specific mechanism by which H2S improves the progression of atrial fibrosis to AF remains unclear. A case-control study of patients with and without AF was designed to assess changes in H2S, the Warburg effect, and ERS in AF. The results showed that AF can significantly reduce cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate thiotransferase (3-MST) expression and the H2S level, induce cystathionine-ß-synthase (CBS) expression; increase the Warburg effect, ERS and atrial fibrosis; and promote left atrial dysfunction. In addition, AngII-treated SD rats had an increased Warburg effect and ERS levels and enhanced atrial fibrosis progression to AF compared to wild-type SD rats, and these conditions were reversed by sodium hydrosulfide (NaHS), dichloroacetic acid (DCA) or 4-phenylbutyric acid (4-PBA) supplementation. Finally, low CSE levels in AngII-induced HL-1 cells were concentration- and time-dependent and associated with mitochondrial dysfunction, apoptosis, the Warburg effect and ERS, and these effects were reversed by NaHS, DCA or 4-PBA supplementation. Our research indicates that H2S can regulate the AngII-induced Warburg effect and ERS and might be a potential therapeutic drug to inhibit atrial fibrosis progression to AF.

The Role of Ubiquitin E3 Ligase in Atherosclerosis.

Atherosclerosis is a chronic inflammatory vascular disease. Atherosclerotic cardiovascular disease is the main cause of death in both developed and developing countries. Many pathophysiological factors, including abnormal cholesterol metabolism, vascular inflammatory response, endothelial dysfunction and vascular smooth muscle cell proliferation and apoptosis, contribute to the development of atherosclerosis and the molecular mechanisms underlying the development of atherosclerosis are not fully understood. Ubiquitination is a multistep post-translational protein modification that participates in many important cellular processes. Emerging evidence suggests that ubiquitination plays important roles in the pathogenesis of atherosclerosis in many ways, including regulation of vascular inflammation, endothelial cell and vascular smooth muscle cell function, lipid metabolism and atherosclerotic plaque stability. This review summarizes important contributions of various E3 ligases to the development of atherosclerosis. Targeting ubiquitin E3 ligases may provide a novel strategy for the prevention of the progression of atherosclerosis.

S100 proteins in atherosclerosis.

Atherosclerosis is an arterial disease associated with dyslipidemia, abnormal arterial calcification and oxidative stress. It has been shown that a continued chronic inflammatory state of the arterial wall contributes to the development of atherosclerosis. The inflammatory stimulation, recruitment of inflammatory cells and production of pro-inflammatory cytokines enhances vascular inflammation. Some members of the S100 proteins family bind with their receptors, such as advanced glycation end products (RAGE), scavenger receptors (CD36) and toll-like receptor 4 (TLR-4), contributing to the cellular response in atherosclerotic progression. This review summarizes the roles of S100 proteins (S100A8, S100A9 and S100A12) in the vascular inflammation, vascular calcification and vascular oxidative stress. S100 proteins are released from monocytes, smooth muscle cells and endothelial cells in response to cellular stress stimuli, and then the binding of S100 proteins to RAGE activate downstream signaling such as transcription factor kappa B (NF-κB) translocation and reactive oxygen species (ROS) production, which act as a positive feedback loop for inducing pro-inflammatory phenotype in a wide variety of cell types including endothelial cells, vascular smooth muscle cells and leukocytes. Thus, it suggests that the inhibition of S100 proteins-mediated RAGE and TLR4 activation appears to be a promising approach to treat atherosclerosis. In addition, recent study showed that serum S100A12 can predict future cardiovascular events, highlighting that S100A12 is likely to be a potential biomarker of therapeutic efficacy and disease progression in coronary heart disease. Future studies of patients with coronary heart disease may provide more evidences supporting that S100 proteins is promising drug target in the prevention and therapy of atherosclerosis.

SUMOylation in atherosclerosis.

Atherosclerosis (AS) is the pathophysiologic basis of many cardiovascular diseases. A number of studies have shown that post-translational modification (PTM) contributes to the initiation and progression of AS. For example, recent studies found that SUMOylation, ie, small ubiquitin-like modifier (SUMO) conjugation to target substrate proteins, was involved in AS. This PTM appears related to endothelial cell dysfunction (ECD), dyslipidemia and vascular smooth muscle cell (VSMC) proliferation. This review focuses on the molecular effects of SUMOylation in the initiation and progression of AS, including ECD, dyslipidemia and VSMC proliferation to better understand this pathologic process.

Macrophage polarization in atherosclerosis.

Atherosclerosis is a chronic inflammatory response that increases the risk of cardiovascular diseases. An in-depth study of the pathogenesis of atherosclerosis is critical for the treatment of atherosclerotic cardiovascular disease. The development of atherosclerosis involves many cells, such as endothelial cells, vascular smooth muscle cells, macrophages, and others. The considerable effects of macrophages in atherosclerosis are inextricably linked to macrophage polarization and the resulting phenotype. Moreover, the significant impact of macrophages on atherosclerosis depend not only on the function of the different macrophage phenotypes but also on the relative ratio of different phenotypes in the plaque. Research on atherosclerosis therapy indicates that the reduced plaque size and enhanced stability are partly due to modulating macrophage polarization. Therefore, regulating macrophage polarization and changing the proportion of macrophage phenotypes in plaques is a new therapeutic approach for atherosclerosis. This review provides a new perspective for atherosclerosis therapy by summarizing the relationship between macrophage polarization and atherosclerosis, as well as treatment targeting macrophage polarization.

The emerging roles of extracellular vesicles in diabetes and diabetic complications.

Diabetes and diabetic vascular complications are now the leading cause of death in the world. The effects of traditional medical treatment are usually limited and accompanied by many side effects, such as hypoglycemia, obesity, liver and kidney damage, and gastrointestinal adverse reactions. Thus, it is urgent to explore some new strategies for the treatment of patients with diabetes. Recently, extracellular vesicles have received increased attention because of their emerging roles of cell-to-cell communication under physiological and pathological conditions. In addition, because of their abundant existence in almost all body fluids, as well as their plentiful cargos of bioactive proteins and miRNAs they carry, extracellular vesicles have a strong potential for therapeutic and diagnostic applications in many metabolic diseases, such as obesity and insulin resistance. Here, with the aim of providing the basis for the development of new treatments for diabetes, we review current understanding of extracellular vesicles and the critical roles it has played in the onset and progression of diabetes and diabetic complications.

Fibroblast growth factor-21 alleviates hypoxia/reoxygenation injury in H9c2 cardiomyocytes by promoting autophagic flux.

Fibroblast growth factor (FGF)­21, a member of the family of FGFs, exhibits protective effects against myocardial ischemia and ischemia/reperfusion injury; it is also an enhancer of autophagy. However, the mechanisms underlying the protective role of FGF­21 against cardiomyocyte hypoxia/reoxygenation (H/R) injury remain unclear. The present study aimed to investigate the effect of FGF­21 on H9c2 cardiomyocyte injury induced by H/R and the mechanism associated with changes in autophagy. Cultured H9c2 cardiomyocytes subjected to hypoxia were treated with a vehicle or FGF­21 during reoxygenation. The viability of H9c2 rat cardiomyocytes was measured using Cell Counting Kit­8 and trypan blue exclusion assays. The contents of creatine kinase (CK) and creatine kinase isoenzymes (CK­MB), cardiac troponin I (cTnT), cardiac troponin T (cTnI) and lactate dehydrogenase (LDH) in culture medium were detected with a CK, CK­MB, cTnT, cTnI and LDH assay kits. The protein levels were examined by western blot analysis. Autophagic flux was detected by Ad­mCherry­GFP­LC3B autophagy fluorescent adenovirus reagent. The results indicated that FGF­21 alleviated H/R­induced H9c2 myocardial cell injury and enhanced autophagic flux during H/R, and that this effect was antagonized by co­treatment with 3­methyladenine, an autophagy inhibitor. Furthermore, FGF­21 increased the expression levels of Beclin­1 and Vps34 proteins, but not of mechanistic target of rapamycin. These data indicate that FGF­21 treatment limited H/R injury in H9c2 cardiomyocytes by promoting autophagic flux through upregulation of the expression levels of Beclin­1 and Vps34 proteins.

Endothelial to mesenchymal transition in atherosclerotic vascular remodeling.

Endothelial cells are the main components of the heart, blood vessels, and lymphatic vessels, which play an important role in regulating the physiological functions of the cardiovascular system. Endothelial dysfunction is involved in a variety of acute and chronic cardiovascular diseases. As a special type of epithelial-mesenchymal transition (EMT), endothelium to mesenchymal transition (EndMT) regulates the transformation of endothelial cells into mesenchymal cells accompanied by changes in the expression of various transcription factors and cytokines, which is closely related to vascular endothelial injury, vascular remodeling, myocardial fibrosis and valvar disease. Endothelial cells undergoing EndMT lose their endothelial characteristics and undergo a transition toward a more mesenchymal-like phenotype. However, the molecular mechanism of EndMT remains unclear. EndMT, as a type of endothelial dysfunction, can cause vascular remodeling which is a major determinant of atherosclerotic luminal area. Therefore, exploring the important signaling pathways in the process of EndMT may provide novel therapeutic strategies for treating atherosclerotic diseases.

Tissue factor pathway inhibitor in atherosclerosis.

Tissue factor pathway inhibitor (TFPI) reduces the development of atherosclerosis by regulating tissue factor (TF) mediated coagulation pathway. In this review, we focus on recent findings on the inhibitory effects of TFPI on endothelial cell activation, vascular smooth muscle cell (VSMC) proliferation and migration, inflammatory cell recruitment and extracellular matrix which are associated with the development of atherosclerosis. Meanwhile, we are also concerned about the impact of TFPI levels and genetic polymorphisms on clinical atherogenesis. This article aims to explain the mechanism in inhibiting the development of atherosclerosis and clinical effects of TFPI, and provide new ideas for the clinical researches and mechanism studies of atherothrombosis.

Role of autophagy in advanced atherosclerosis (Review).

Atherosclerosis (AS) remains the leading cause for global cardiovascular disease morbidity and mortality, and a major cause of cardiopathy, myocardial infarction and peripheral vascular diseases. Macrophages serve a critical role in atherosclerotic plaque stabilization and rupture, and the selective removal of macrophages may be beneficial in improving plaque stability. Autophagy is a process of self­feeding, during which cytoplasmic proteins or organelles are packaged into vesicles and fused with the lysosome to form an autophagosome. The newly formed autophagosome can degrade internalized proteins, and this process may be used to serve the metabolic and self­renewal requirements of the cell. Autophagy serves an important role in maintaining cell homeostasis and promoting cell survival, and therefore an imbalance in autophagy is closely associated with multiple diseases.