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. The cannabinoid receptor ligand anandamide and its metabolically stable analog, R-methanandamide, suppressed hypertrophic indicators including cardiomyocyte enlargement and fetal gene activation (ie, the brain natriuretic peptide 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 brain natriuretic peptide 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 short hairpinRNA knockdown, and eNOS inhibition using L-NIO abolished the antihypertrophic actions of CB-13. In conclusion, CB-13 inhibits cardiomyocyte hypertrophy through AMPK-eNOS signaling and may represent a novel therapeutic approach to cardioprotection.

• Authors: Yan Lu, Bolanle C Akinwumi, Zongjun Shao, Hope D Anderson
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 64 Issue 5 Pg. 420-30 (Nov 2014) ISSN: 1533-4023 [Electronic] United States
• PMID: 24979612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arachidonic Acids
• Cannabinoid Receptor Agonists
• Cannabinoids
• Cardiotonic Agents
• Endocannabinoids
• Endothelin-1
• Ligands
• Naphthalenes
• Polyunsaturated Alkamides
• Receptor, Cannabinoid, CB1
• Receptor, Cannabinoid, CB2
• methanandamide
• naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone
• Nitric Oxide Synthase Type III
• AMP-Activated Protein Kinases
• 1,1-dimethylbutyl-1-deoxy-Delta(9)-THC
• anandamide

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Animals, Newborn
• Arachidonic Acids (pharmacology)
• Cannabinoid Receptor Agonists (pharmacology)
• Cannabinoids (pharmacology)
• Cardiomegaly (drug therapy, pathology)
• Cardiotonic Agents (pharmacology)
• Endocannabinoids (pharmacology)
• Endothelin-1 (metabolism)
• Gene Knockdown Techniques
• Ligands
• Male
• Myocytes, Cardiac (drug effects, pathology)
• Naphthalenes (pharmacology)
• Nitric Oxide Synthase Type III (metabolism)
• Polyunsaturated Alkamides (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Cannabinoid, CB1 (drug effects, metabolism)
• Receptor, Cannabinoid, CB2 (drug effects, metabolism)
• Signal Transduction (drug effects)