2014 Jun 26. [Epub ahead of print]
Ligand Activation of Cannabinoid Receptors Attenuates Hypertrophy of Neonatal Rat Cardiomyocytes.
Abstract
Endocannabinoids are bioactive amides, esters and ethers of long chain polyunsaturated fatty acids. Evidence suggests that activation of the endocannabinoid pathway offers cardioprotection against myocardial ischemia, arrhythmias, and endothelial dysfunction of coronary arteries. As cardiac hypertrophy is a convergence point of risk factors for heart failure, we determined a role for endocannabinoids in attenuating endothelin-1-induced hypertrophy, and probed the signaling pathways involved. Thecannabinoid receptor ligand anandamide and its metabolically-stable analog, R-methanandamide, suppressed hypertrophic indicators including cardiomyocyte enlargement and fetal gene activation (i.e. the brain natriuretic peptide [BNP] gene) elicited by endothelin-1 in isolated neonatal rat ventricular myocytes. The ability of R-methanandamide to suppress myocyte enlargement and fetal gene activation was mediated by CB2 and CB1 receptors, respectively. Accordingly, a CB2-selective agonist, JWH-133, prevented only myocyte enlargement but not BNP gene activation. A CB1/CB2 dual agonist with limited brain penetration, CB-13, inhibited both hypertrophic indicators. CB-13 activated AMP-activated protein kinase (AMPK) and, in an AMPK-dependent manner, endothelial nitric oxide synthase (eNOS). Disruption of AMPK signaling, using compound C or shRNA knockdown, and eNOS inhibition using L-NIO abolished the anti-hypertrophic actions of CB-13. In conclusion, CB-13 inhibits cardiomyocyte hypertrophy via AMPK-eNOS signaling and may represent a novel therapeutic approach to cardioprotection.
- PMID:
24979612
[PubMed – as supplied by publisher]
