Mitochondrial KATP channel involvement in angiotensin II-induced autophagy in vascular smooth muscle cells.
Autophagy has emerged as a powerful process in the response to cellular injury. The present study was designed to investigate signal transduction pathways in angiotensin II (Ang II)-induced autophagy. Rat vascular smooth muscle cells (VSMCs) were stimulated with different doses of Ang II (10(-9)-10(-5) mol/L) for different time periods (6-72 h). Incubation with Ang II increased the production of reactive oxygen species (ROS), increased the LC3-II to LC3-I ratio, increased beclin-1 expression, and decreased SQSTM1/p62 expression in a dose- and time-dependent manner. In addition, Ang II increased autophagosome formation. Increased ROS production induced by Ang II was inhibited by Ang II type 1 receptor (AT1) blockers (Olmesartan and Candesartan, ARB), a NADPH Oxidase inhibitor (apocynin), and mitochondrial KATP channels inhibitor (5-hydroxydecanoate, 5HD). Ang II (10(-7) mol/L, 48 h)-induced increase in the LC3-II to LC3-I ratio, the formation of autophagosomes, expression of beclin-1 and decrease in the expression of SQSTM1/p62 were also inhibited by pretreatment with 3-methyladenine or bafilomycin A1 (inhibitors of autophagy), olmesartan and candesartan (in dose-dependent manners), apocynin, 5HD, and siRNA Atg5. Our results indicate that Ang II increases autophagy levels via activation of AT1 receptor and NADPH oxidase. Mitochondrial KATP channels also play an important role in Ang II-induced autophagy. Our results may provide a new strategy for treatment of cardiovascular diseases with Ang II.
Department of Physiology, Medical College of Soochow University, 199 Ren-Ai Road, Dushu Lake Campus, Suzhou Industrial Park, Suzhou, 215123, People's Republic of China.
Kang-Ying
KY
Yu
Ya-Ping
YP
Wang
Lin-Hui
LH
Wang
Yang
Y
Jian
Xiao-Dong
XD
Zhao
Jing-Wei
JW
Chen
Koji
K
Murao
Wei
W
Zhu
Liang
L
Dong
Guo-Qing
GQ
Wang
Guo-Xing
GX
Zhang
D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D008869:Microtubule-Associated Proteins; D019255:NADPH Oxidases; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011506:Proteins; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D000071456:Sequestosome-1 Protein; C545865:Atg5 protein, rat; C512829:Becn1 protein, rat; C526109:Anxa3 protein, rat; C491079:Sqstm1 protein, rat; C117780:mitochondrial K(ATP) channel