Activation of Endocannabinoid Receptor 2 as a Mechanism of Propofol Pretreatment‐Induced Cardioprotection against Ischemia‐Reperfusion Injury in Rats

Abstract

Propofol pretreatment before reperfusion, or propofol conditioning, has been shown to be cardioprotective, while its mechanism is unclear. The current study investigated the roles of endocannabinoid signaling in propofol cardioprotection in an in vivo model of myocardial ischemia/reperfusion (I/R) injury and in in vitro primary cardiomyocyte hypoxia/reoxygenation (H/R) injury. The results showed that propofol conditioning increased both serum and cell culture media concentrations of endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) detected by LC-MS/MS. The reductions of myocardial infarct size in vivo and cardiomyocyte apoptosis and death in vitro were accompanied with attenuations of oxidative injuries manifested as decreased reactive oxygen species (ROS), malonaldehyde (MDA), and MPO (myeloperoxidase) and increased superoxide dismutase (SOD) production. These effects were mimicked by either URB597, a selective endocannabinoids degradation inhibitor, or VDM11, a selective endocannabinoids reuptake inhibitor. In vivo study further validated that the cardioprotective and antioxidative effects of propofol were reversed by selective CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251. We concluded that enhancing endogenous endocannabinoid release and subsequent activation of CB2 receptor signaling represent a major mechanism whereby propofol conditioning confers antioxidative and cardioprotective effects against myocardial I/R injury.

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

“…In support of these findings, the cytoprotective effect of propofol is abolished by CB2 antagonists, although not by CB1 antagonists [118]. An effect similar to propofol is exhibited by an FAAH inhibitor (URB597) and an endocannabinoid reuptake inhibitor (VDM11) [118]. In addition, the exposure of neurons to another endocannabinoid-oleoylethanolamine (OEA)-also exerts a neuroprotective effect, in a manner dependent on the PPARα receptors of hypoxic neurons, which would otherwise cause their apoptosis, in part by increasing Bax expression and decreasing Bcl-2 levels [119,120].…”

“…This is accompanied by increased activation of CB1 and CB2 receptors at both mRNA and protein levels. In support of these findings, the cytoprotective effect of propofol is abolished by CB2 antagonists, although not by CB1 antagonists [118]. An effect similar to propofol is exhibited by an FAAH inhibitor (URB597) and an endocannabinoid reuptake inhibitor (VDM11) [118].…”

The effect of high maternal linoleic acid on endocannabinoid signalling in rodent hearts

“…CB 2 receptor expression in non-pregnant females has been demonstrated to be cardioprotective, with up-regulation decreasing risk of cardiovascular diseases. 29 In further support of a beneficial role for CB 2 , the activation of the receptor increases the production of anti-inflammatory proteins. 30 Although we have not investigated cardiovascular function in mothers consuming elevated LA diets and circulating concentrations of proinflammatory cytokines appear unaltered, 3 the current data suggest that elevated LA during pregnancy may modify maternal cardiovascular function.…”

Modulation of the Oxidative Stress and Lipid Peroxidation by Endocannabinoids and Their Lipid Analogues

“…The involvement of CB2 in I/R injury has also been investigated in a context of propofol cardioprotection in an in vivo model of myocardial I/R injury, in which it has been observed that CB2 inactivation reverses propofol cardioprotective and anti-oxidative effects [ 230 ]. These findings imply that the enhancement of ECs release and the subsequent activation of CB2 signaling are responsible for the reduced oxidative stress mediated by propofol cardioprotection in myocardial I/R injury [ 230 ].…”