Activation of Cannabinoid Receptors Attenuates Endothelin-1–Induced Mitochondrial Dysfunction in Rat Ventricular Myocytes

Abstract

Evidence suggests that the activation of the endocannabinoid system offers cardioprotection. Aberrant energy production by impaired mitochondria purportedly contributes to various aspects of cardiovascular disease. We investigated whether cannabinoid (CB) receptor activation would attenuate mitochondrial dysfunction induced by endothelin-1 (ET1). Acute exposure to ET1 (4 hours) in the presence of palmitate as primary energy substrate induced mitochondrial membrane depolarization and decreased mitochondrial bioenergetics and expression of genes related to fatty acid oxidation (ie, peroxisome proliferator–activated receptor-gamma coactivator-1α, a driver of mitochondrial biogenesis, and carnitine palmitoyltransferase-1β, facilitator of fatty acid uptake). A CB1/CB2 dual agonist with limited brain penetration, CB-13, corrected these parameters. AMP-activated protein kinase (AMPK), an important regulator of energy homeostasis, mediated the ability of CB-13 to rescue mitochondrial function. In fact, the ability of CB-13 to rescue fatty acid oxidation–related bioenergetics, as well as expression of proliferator-activated receptor-gamma coactivator-1α and carnitine palmitoyltransferase-1β, was abolished by pharmacological inhibition of AMPK using compound C and shRNA knockdown of AMPKα1/α2, respectively. Interventions that target CB/AMPK signaling might represent a novel therapeutic approach to address the multifactorial problem of cardiovascular disease.

Cannabinoid Receptor Agonist Inhibits Atrial Electrical Remodeling in a Tachypaced Ex Vivo Rat Model

“…The present study extends extant evidence indicating possible beneficial effects of ECS activation in the stressed myocardium (Wagner et al, 2001;Lu et al, 2014;Lu et al, 2020). Overall, this study demonstrated three salient findings regarding the cardiac effects of the peripherally restricted, dual CBR agonist CB13 in rats: 1) lack of CB13-dependent chronotropic, dromotropic or hemodynamic effects in the non-paced ex-vivo preparation; 2) an ability of CB13 to antagonize the AERP remodelling induced by acute atrial tachypacing; 3) AMPK activation may contribute to the ability of CB13 to protect against tachypacing-induced atrial remodelling.…”

“…However, CB13 treatment caused a significant upregulation of PGC-1α. We previously speculated that CB13 activates AMPK via CB2R whereas CB1 receptors invoke other signaling pathways (Lu et al, 2020). In addition, Zheng et al demonstrated that JWH-133, a CB2Rselective agonist, adequately activated AMPK to stimulate PGC-1α, without CB1R interaction (Zheng et al, 2013).…”

“…Treatments remained in buffer for the remainder of the experiment. The concentration of CB13 was based on our previous findings in cardiomyocytes in vitro (Lu et al, 2014;Lu et al, 2020).…”

“…In conclusion, our data demonstrating the ability of CB13 treatment to prevent tachypacing-induced AERP shortening and Cx43 reduction, as well as to activate known cardioprotective signaling mediators in terms of metabolic dysfunction (i.e., AMPK and PGC-1 α), are collectively in favor of a putative beneficial effect of this drug as a new upstream modality that might be utilized to prevent atrial electrical remodeling. Considering the possible beneficial effects of such treatment in the context of pathological hypertrophy (Lu et al, 2014;Lu et al, 2020), which shares many of the risk factors for AF, this therapeutic strategy is even more attractive for further investigation.…”

“…Using CB13, a CB1R and CB2R dual agonist that does not cross the blood-brain barrier, we previously reported antihypertrophic effects and attenuated mitochondrial dysfunction in cardiomyocytes via activation of AMPK signaling pathways (Lu et al, 2014;Lu et al, 2020). We hypothesize that the beneficial effects of CB13 may be relevant to stressed atria as well.…”