title: Regulation of autophagy and apoptosis in response to ox-LDL in vascular smooth muscle cells, and the modulatory effects of the microRNA hsa-let-7 g.
abstract: OBJECTIVE
  Regulation of autophagy and apoptosis during treatment of vascular smooth muscle cells (VSMCs) with pro-atherogenic stimuli, such as oxidized low density lipoprotein (ox-LDL), remains unclear.
  
  
  RESULTS
  We examined the expression of autophagy and apoptosis upon treatment of VSMCs with ox-LDL. Exposure to ox-LDL in modest amounts (10-40 μg/ml) enhanced autophagy (expression of beclin-1, LC3-II/LC3-1 ratio and Atg5) and apoptosis (expression of caspase-3, Bax, Bcl-2 and Bcl-xL); however, exposure to higher concentrations (≥ 60 μg/ml) induced high levels of apoptosis but autophagy declined. Pretreatment of VSMCs with the miRNA hsa-let-7 g inhibited autophagy, as LOX-1 expression and apoptosis declined. Hsa-let-7 g treatment also resulted in a decrease in intracellular ROS generation. Treatment with LOX-1 antibody had similar effects as hsa-let-7 g. Next, we studied autophagy and apoptosis in aortic segments from wild-type and LOX-1 knockout mice fed a high cholesterol diet, and observed increased autophagy as well as apoptosis in lipid-rich sections of aortas from wild-type mice and LOX-1 knockout mice (vs. corresponding controls); however, both autophagy and apoptosis in lipid-rich areas in aortic sections of LOX-1 knockout mice were less than in WT mice. These in vivo data are in keeping with in vitro data showing enhanced autophagy and apoptosis of VSMCs exposed to modest amount of ox-LDL.
  
  
  CONCLUSIONS
  This study provides first set of data on the regulation of autophagy and apoptosis in ox-LDL-treated VSMCs. Our observations also suggest that hsa-let-7 g acts as a critical regulator of autophagy and apoptosis by modulating LOX-1.
authors.affiliation: Central Arkansas Veterans Healthcare System and the Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Zufeng
authors.initials: Z
authors.lastname: Ding
authors.forename: Xianwei
authors.initials: X
authors.lastname: Wang
authors.forename: Laura
authors.initials: L
authors.lastname: Schnackenberg
authors.forename: Magomed
authors.initials: M
authors.lastname: Khaidakov
authors.forename: Shijie
authors.initials: S
authors.lastname: Liu
authors.forename: Sandeep
authors.initials: S
authors.lastname: Singla
authors.forename: Yao
authors.initials: Y
authors.lastname: Dai
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001343:Autophagy / Q000235:genetics*; D002478:Cells, Cultured; D006801:Humans; D008077:Lipoproteins, LDL / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology
chemical_list: D008077:Lipoproteins, LDL; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; C099252:oxidized low density lipoprotein
keywords: Autophagy; LOX-1; ROS; Smooth muscle cells; hsa-let-7g