sirolimus and 7-ketocholesterol

The vulnerable plaque is a key distinguishing feature of atherosclerotic lesions that can cause acute atherothrombotic vascular disease. This study was designed to explore the effect of autophagy on mitochondria-mediated macrophage apoptosis and vulnerable plaques. Here, we generated the mouse model of vulnerable carotid plaque in ApoE

Topics: Animals; Apolipoproteins E; Apoptosis; Autophagy; Disease Progression; Ketocholesterols; Macrophages; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mitochondria; Models, Biological; Necrosis; NF-kappa B; Plaque, Atherosclerotic; RAW 264.7 Cells; Sirolimus

Oxidized lipoproteins stimulate autophagy in advanced atherosclerotic plaques. However, the mechanisms underlying autophagy induction and the role of autophagy in atherogenesis remain to be determined. This study was designed to investigate the mechanisms by which 7-ketocholesterol (7-KC), a major component of oxidized lipoproteins, induces autophagy. This study was also designed to determine the effect of autophagy induction on apoptosis, a central event in the development of atherosclerosis. Exposure of human aortic smooth muscle cells to 7-KC increased autophagic flux. Autophagy induction was suppressed by treating the cells with either a reactive oxygen species scavenger or an antioxidant. Administration of 7-KC concomitantly up-regulated Nox4 expression, increased intracellular hydrogen peroxide levels, and inhibited autophagy-related gene 4B activity. Catalase overexpression to remove hydrogen peroxide or Nox4 knockdown with siRNA reduced intracellular hydrogen peroxide levels, restored autophagy-related gene 4B activity, and consequently attenuated 7-KC-induced autophagy. Moreover, inhibition of autophagy aggravated both endoplasmic reticulum (ER) stress and cell death in response to 7-KC. In contrast, up-regulation of autophagic activity by rapamycin had opposite effects. Finally, activation of autophagy by chronic rapamycin treatment attenuated ER stress, apoptosis, and atherosclerosis in apolipoprotein E knockout (ApoE(-/-)) mouse aortas. In conclusion, we demonstrate that up-regulation of autophagy is a cellular protective response that attenuates 7-KC-induced cell death in human aortic smooth muscle cells.

Topics: Animals; Aorta; Apoptosis; Atherosclerosis; Autophagy; Autophagy-Related Proteins; Cardiovascular Agents; Cell Death; Cells, Cultured; Cysteine Endopeptidases; Enzyme Inhibitors; Free Radical Scavengers; Humans; Hydrogen Peroxide; Ketocholesterols; Male; Mice; Microtubule-Associated Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NADPH Oxidase 4; NADPH Oxidases; Reactive Oxygen Species; Sirolimus; Up-Regulation