Autophagy plays a protective role in free cholesterol overload-induced death of smooth muscle cells

Xu, Kedi; Yang, Yi; Yan, M.; Zhan, Junpeng; Fu, Xiao; Zheng, Xiaoxiang

doi:10.1194/jlr.m005702

Cited by 69 publications

(50 citation statements)

References 32 publications

(32 reference statements)

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“…42 For example, inhibition of autophagy using 3-methyladenine in free cholesterol-treated SMCs enhances apoptosis and necrosis. 29 Moreover, in vivo experiments confirmed that the inactivation of Atg genes can cause apoptotic cell death. 43 Autophagy proteins can also exert proapoptotic functions by themselves.…”

Section: Schrijvers Et Al Autophagy In Atherosclerosis 2789mentioning

confidence: 82%

“…27 Also, excess free cholesterol or exposure of SMCs to lipid peroxidation products, such as 4-hydroxynonenal, activates autophagy, thereby prolonging SMC survival. 28,29 Similar to SMCs, exposure of endothelial cells in culture to oxidized lipoproteins or advanced glycation end-products induces autophagy, 14,15 which is protective against endothelial cell injury. 30 Altogether, induction of autophagy represents a vital component of a general stress response in vascular cells and could therefore be an important determinant of the stability of atherosclerotic plaques ( Figure 2).…”

Section: Beneficial Role Of Autophagy In Atherosclerosismentioning

confidence: 99%

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Autophagy in Atherosclerosis

Schrijvers

Meyer

Martinet

2011

ATVB

161

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Abstract-Evidence is accumulating that autophagy occurs in advanced atherosclerotic plaques. Although there is an almost relentless discovery of molecules that are involved in autophagy, studies of selective autophagy induction or inhibition using knockout mice are just now beginning to reveal its biological significance. Most likely, autophagy safeguards plaque cells against cellular distress, in particular oxidative injury, by degrading the damaged intracellular material. In this way, autophagy is protective and contributes to cellular recovery in an unfavorable environment. Pharmacological approaches have recently been developed to stabilize vulnerable, rupture-prone lesions through induction of autophagy. This approach has proven to be successful in short-term studies. However, how autophagy induction affects processes such as inflammation remains to be elucidated and is currently under investigation. This review highlights the possibilities for exploiting autophagy as a drug target for plaque stabilization. Key Words: atherosclerosis Ⅲ pharmacology Ⅲ autophagy Ⅲ cell death Ⅲ plaque stabilization A utophagy, or "self eating," refers to a conserved cellular process for the turnover of organelles and proteins that occurs in all eukaryotic cells. 1 It is activated as an adaptive response to environmental stress (eg, nutrient deprivation, hypoxia, oxidative stress, exposure to xenobiotics) to promote cell survival through the recycling of precursors (amino acids, free fatty acids, nucleotides) derived from the degradation of endogenous cellular components. Typical of autophagy is the formation of double-membrane structures, called phagophores, that engulf intracellular material such as protein aggregates, lipid droplets, and complete organelles for degradation (Figure 1). The phagophore expands and, on completion, forms an autophagosome, which then fuses with lysosomes, thereby generating an autophagolysosome. 2 Incorporation of the outer autophagosomal membrane in the lysosomal membrane allows the degradation of the remaining inner single membrane and the cytoplasmic content of the autophagosome by lysosomal hydrolases. The molecular machinery and the signaling cascades that regulate autophagy are very complex and beyond the scope of this review, but they are nicely reviewed elsewhere. 3,4 Autophagy generally acts as a housekeeping mechanism, and it is crucially involved in the maintenance of normal cellular homeostasis. When stimulated by cellular stress conditions, autophagy functions as a self-cannibalization pathway that promotes cell survival in an unfavorable environment. Preclinical studies have demonstrated that autophagy is associated with cancer, neurodegenerative disorders (eg, Alzheimer, Parkinson, and Huntington diseases), embryogenesis, aging, and immunity, and also with cardiovascular disease, including ischemia-reperfusion injury of the heart, cardiomyopathy, and atherosclerosis. 5-9 Despite tremendous recent advances in the field, the functional significance of autophagy in human disease remain...

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Section: Schrijvers Et Al Autophagy In Atherosclerosis 2789mentioning

confidence: 82%

Section: Beneficial Role Of Autophagy In Atherosclerosismentioning

confidence: 99%

Autophagy in Atherosclerosis

Schrijvers

Meyer

Martinet

2011

ATVB

161

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“…Studies indicate a protective role of autophagy against atherosclerosis in SMCs. Autophagy protects SMCs in vitro against oxidized lipids and excess free cholesterol, while inhibition of autophagy triggers cell death (62,157).…”

Section: Autophagy In Cell Types Beyond the Cardiomyocytementioning

confidence: 99%

Unbreak My Heart: Targeting Mitochondrial Autophagy in Diabetic Cardiomyopathy

Kubli

Gustafsson

2015

Antioxidants & Redox Signaling

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Significance: Diabetes is strongly associated with increased incidence of heart disease and mortality due to development of diabetic cardiomyopathy. Even in the absence of cardiovascular disease, cardiomyopathy frequently arises in diabetic patients. Current treatment options for cardiomyopathy in diabetic patients are the same as for nondiabetic patients and do not address the causes underlying the loss of contractility. Recent Advances: Although there are numerous distinctions between Type 1 and Type 2 diabetes, recent evidence suggests that the two disease states converge on mitochondria as an epicenter for cardiomyocyte damage. Critical Issues: Accumulation of dysfunctional mitochondria contributes to cardiac tissue injury in both acute and chronic conditions. Removal of damaged mitochondria by macroautophagy, termed ''mitophagy,'' is critical for maintaining cardiomyocyte health and contractility both under normal conditions and during stress. However, very little is known about the involvement of mitophagy in the pathogenesis of diabetic cardiomyopathy. A growing interest in this topic has given rise to a wave of publications that aim at deciphering the status of autophagy and mitophagy in Type 1 and Type 2 diabetes. Future Directions: This review summarizes these recent studies with the goal of drawing conclusions about the activation or suppression of autophagy and mitophagy in the diabetic heart. A better understanding of how autophagy and mitophagy are affected in the diabetic myocardium is still needed, as well as whether they can be targeted therapeutically. Antioxid. Redox Signal. 22, 1527Signal. 22, -1544

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“…An overload of free cholesterol, for example, triggers autophagy in SMCs as illustrated by increased formation of autophagic vacuoles and conversion of microtubule-associated protein 1 light chain 3 (LC3)-I into the autophagosome-specific LC3-II and promotes SMC survival, possibly by improving the clearance of damaged organelles. 31 Inhibition of autophagy by treatment with 3-methyladenine leads to increased ER stress and mitochondrial depolarization, whereas rapamycin treatment reduces ER stress by stimulating autophagy. Autophagy in SMCs may also be activated by cytokines and growth factors.…”

Section: Autophagy In the Normal Vessel Wall Autophagy Is A Cytoprotementioning

confidence: 99%

Autophagy in Vascular Disease

Meyer

Grootaert

Michiels

et al. 2015

Circulation Research

247

179

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A utophagy is a complex intracellular process that delivers cytoplasmic constituents for degradation into lysosomes.1,2 Three main types of autophagy have been described: (1) microautophagy, comprising direct engulfment of cytoplasmic material by lysosomes via inward invaginations of the lysosomal membrane, (2) macroautophagy, characterized by formation of double-membrane sequestering compartments termed autophagosomes that fuse with lysosomes for delivery of cytoplasmic cargo, and (3) chaperone-mediated autophagy, mediated by a chaperone complex and lysosomal-associated membrane protein type 2A to degrade cytosolic proteins with a specific targeting motif. The term autophagy usually refers to macroautophagy, which is the most prevalent and beststudied form of autophagy. Also in this review, we will focus exclusively on macroautophagy, further cited as autophagy.Autophagy occurs at basal levels in most tissues to allow constitutive turnover of cytosolic components but is stimulated by environmental stress-related signals (eg, nutrient deprivation and oxidative injury) to recycle nutrients and to generate energy for maintenance of cell viability in unfavorable conditions.1 In addition to cellular stress, basal autophagy can be intensified by specific drugs, 3 indicating that the autophagic machinery is a potential therapeutic target for diverse diseases. Indeed, given that autophagy is involved in the prevention

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Autophagy plays a protective role in free cholesterol overload-induced death of smooth muscle cells

Abstract: oxygen species; SMC, smooth muscle cell; TEM, transmission electron mic roscopy; mTOR, mammalian target of rapamycin; UPR, unfolded protein response.

Cited by 69 publications

References 32 publications

Autophagy in Atherosclerosis

Autophagy in Atherosclerosis

Unbreak My Heart: Targeting Mitochondrial Autophagy in Diabetic Cardiomyopathy

Autophagy in Vascular Disease

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