title: Propofol Provides Cardiac Protection by Suppressing the Proteasome Degradation of Caveolin-3 in Ischemic/Reperfused Rat Hearts.
abstract: The mechanisms underlying propofol's cardioprotective role remain elusive. Caveolin-3 (Cav-3) has been shown to mediate both opioids- and volatile anesthetics-induced cardioprotection against ischemia/reperfusion (I/R) injury. We hypothesize that the cardioprotective role of propofol is mediated through Cav-3 and its regulation of PI3K/Akt/GSK3β signal pathway. Rats or H9c2 cardiomyocytes were exposed to propofol before I/R or simulated ischemia/reperfusion (SI/R). Propofol pretreatment significantly decreased left ventricle infarct size in vivo (P < 0.05) and terminal deoxynucleotidyl transferase nick-end labeling-positive cells both in vivo and in vitro (P < 0.05), along with an increased Cav-3 protein expression and binding of Cav-3 to p85-subunit of PI3K. No significant change in Cav-3 mRNA expression in left ventricle tissues was found in either I/R or propofol-treated groups. Methyl-β-cyclodextrin or Cav-3 siRNA was used to knockdown Cav-3 expression in vitro, which virtually abolished propofol-induced cardiac protection and PI3K/Akt/GSK3β pathway activation. In contrast, MG132, a proteasome inhibitor, could significantly restore SI/R-induced Cav-3 decrease. It is concluded that Cav-3 mediates propofol-induced cardioprotection against I/R injury and the relevant PI3K/Akt/GSK3β activation. The downregulation of Cav-3 under SI/R may be caused by proteasome degradation, and this process can be prevented by propofol.
authors.affiliation: *Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China; †Department of Anesthesiology, Peking Union Medical College Hospital, CAMS&PUMC, Beijing, People's Republic of China; ‡Department of Cardiology, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; §Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA; and ¶Department of Laboratory Medicine and Pathology, University of Minnesota, MN.
authors.forename: Afang
authors.initials: A
authors.lastname: Zhu
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: You
authors.forename: Shanglong
authors.initials: S
authors.lastname: Yao
authors.forename: Shiying
authors.initials: S
authors.lastname: Yuan
authors.forename: Haodong
authors.initials: H
authors.lastname: Xu
authors.forename: Faqian
authors.initials: F
authors.lastname: Li
authors.forename: Weike
authors.initials: W
authors.lastname: Mao
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051244:Caveolin 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D015742:Propofol / Q000494:pharmacology / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002316:Cardiotonic Agents; C495549:Cav3 protein, rat; D051244:Caveolin 3; D046988:Proteasome Endopeptidase Complex; D015742:Propofol