title: Telmisartan-induced PPARγ activity attenuates lipid accumulation in VSMCs via induction of autophagy.
abstract: Foam cell formation is the hallmark of atherosclerosis. Both telmisartan and autophagy protect against the development of atherosclerosis. However, it has yet to be elucidated whether telmisartan prevents vascular smooth muscle cell (VSMC)-derived foam cell formation. Vascular smooth muscle cells isolated from the thoracic aorta of male C57BL/6J mice were used for this study. To induce foam cell formation, primary VSMCs were incubated in 80 μg/ml oxLDL for 24 h. LC3, beclin-1, PPARγ, AMPK, p-AMPK, mTOR and p-mTOR expression were determined via Western blot. Lipid accumulation was evaluated via oil red O staining and intracellular total cholesterol level measurement. Our study demonstrated that telmisartan dose-dependently increased the expression of beclin-1, the LC3II/LC3I ratio and the quantity of GFP-labeled autophagosomes, displaying a peak effect at 10 μM. In control siRNA-transfected VSMCs, telmisartan (10 μM) decreased lipid droplet accumulation and the total cholesterol level significantly. In contrast, in Atg7 siRNA-transfected VSMCs, telmisartan failed to attenuate lipid accumulation. In addition, telmisartan dose-dependently increased the expression of PPARγ and p-AMPK and decreased the expression of p-mTOR. GW9662 attenuated the telmisartan-induced increase in PPARγ expression, the LC3-II/LC3-I ratio and p-AMPK expression and the telmisartan-induced decrease in p-mTOR expression. Compound C restored mTOR activity and abolished the increase in the LC3-II/LC3-I ratio. Rapamycin significantly reduced p-mTOR expression and increased the LC3-II/LC3-I ratio. In conclusion, this study provides evidence that the chronic pharmacological activation of the PPARγ-mediated autophagy pathway using telmisartan may represent a promising therapeutic strategy for atherosclerosis.
authors.affiliation: Department of Neurology, Daping Hospital, Institute of Surgery Research, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, People's Republic of China.
authors.forename: Bing-Hu
authors.initials: BH
authors.lastname: Li
authors.forename: Shao-Qiong
authors.initials: SQ
authors.lastname: Liao
authors.forename: Yan-Wei
authors.initials: YW
authors.lastname: Yin
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Long
authors.forename: Lu
authors.initials: L
authors.lastname: Guo
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Cao
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Chang-Yue
authors.initials: CY
authors.lastname: Gao
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Zhang
authors.forename: Jing-Cheng
authors.initials: JC
authors.lastname: Li
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077333:Telmisartan
chemical_list: D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase; D000077333:Telmisartan