CB2 Cannabinoid Receptor as a Potential Target in Myocardial Infarction: Exploration of Molecular Pathogenesis and Therapeutic Strategies

Abstract

The lipid endocannabinoid system has recently emerged as a novel therapeutic target for several inflammatory and tissue-damaging diseases, including those affecting the cardiovascular system. The primary targets of cannabinoids are cannabinoid type 1 (CB1) and 2 (CB2) receptors. The CB2 receptor is expressed in the cardiomyocytes. While the pathological changes in the myocardium upregulate the CB2 receptor, genetic deletion of the receptor aggravates the changes. The CB2 receptor plays a crucial role in attenuating the advancement of myocardial infarction (MI)-associated pathological changes in the myocardium. Activation of CB2 receptors exerts cardioprotection in MI via numerous molecular pathways. For instance, delta-9-tetrahydrocannabinol attenuated the progression of MI via modulation of the CB2 receptor-dependent anti-inflammatory mechanisms, including suppression of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1β. Through similar mechanisms, natural and synthetic CB2 receptor ligands repair myocardial tissue damage. This review aims to offer an in-depth discussion on the ameliorative potential of CB2 receptors in myocardial injuries induced by a variety of pathogenic mechanisms. Further, the modulation of autophagy, TGF-β/Smad3 signaling, MPTP opening, and ROS production are discussed. The molecular correlation of CB2 receptors with cardiac injury markers, such as troponin I, LDH1, and CK-MB, is explored. Special attention has been paid to novel insights into the potential therapeutic implications of CB2 receptor activation in MI.

Re-evaluation of the cardioprotective effects of cannabinoids against ischemia-reperfusion injury according to the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria

“…On the other hand, CB 2 receptor activation mainly has a beneficial effect by an influence opposite in direction to that of the CB 1 Rs ( Pacher et al, 2018 ; Smoum et al, 2022 ). However, despite previously observed cardioprotective effects mediated mainly via CB 2 receptor activation [for review, see ( Lamontagne et al, 2006 ; Pacher and Haskó, 2008 ; Steffens and Pacher, 2012 ; Maslov et al, 2016 ; Tang et al, 2021 ; Rorabaugh et al, 2023 ; More et al, 2024 )] the number of studies reporting cardioprotective effects of cannabinoids in different cardiac disorders seems to decline. The previous studies are not even included in the most recent analysis of multitarget strategies proposed to reduce myocardial I/R injury ( Davidson et al, 2019 ; Heusch, 2023 ).…”