title: 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: *Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada; and †Canadian Centre for Agri-Food Research in Health and Medicine, St Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.
authors: Yan
authors: Y
authors: Lu
authors: Bolanle C
authors: BC
authors: Akinwumi
authors: Zongjun
authors: Z
authors: Shao
authors: Hope D
authors: HD
authors: Anderson
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology; D006332:Cardiomegaly / Q000188:drug therapy* / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D063388:Endocannabinoids / Q000494:pharmacology; D019332:Endothelin-1 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D008024:Ligands; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D009281:Naphthalenes / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D002316:Cardiotonic Agents; D063388:Endocannabinoids; D019332:Endothelin-1; D008024:Ligands; D009281:Naphthalenes; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C088155:methanandamide; C524107:naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone; D052250:Nitric Oxide Synthase Type III; D055372:AMP-Activated Protein Kinases; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC; C078814:anandamide