anandamide and Cardiomegaly

The transient receptor potential vanilloid type 1 (TRPV1) is expressed in the cardiovascular system, and increased TRPV1 expression has been associated with cardiac hypertrophy. Nevertheless, the role of TRPV1 in the pathogenesis of cardiac hypertrophy and the underlying molecular mechanisms remain unclear.. In cultured cardiomyocytes, activation of TRPV1 increased cell size and elevated expression of atrial natriuretic peptide mRNA and intracellular calcium level, which was reversed by TRPV1 antagonist capsazepine. Increased expression of phosphorylated calmodulin-dependent protein kinase IIδ and mitogen-activated protein kinases were found in TRPV1 agonist capsaicin-treated cardiomyocytes. Selective inhibitor of calmodulin-dependent protein kinase IIδ decreased phosphorylation of extracellular signal-regulated kinases and p38. Capsaicin induced an increase in expression of ornithine decarboxylase protein, which is the key enzyme in polyamine biosynthesis in cardiomyocytes. Nevertheless, there was no obvious change of ornithine decarboxylase expression in TRPV1 knockdown cells after capsaicin treatment, and specific inhibitors of calmodulin-dependent protein kinase IIδ or p38 downregulated the capsaicin-induced expression of ornithine decarboxylase. Capsazepine alleviated the increase in cross-sectional area of cardiomyocytes and the ratio of heart weight to body weight and improved cardiac function, including left ventricular internal end-diastolic and -systolic dimensions and ejection fraction and fractional shortening percentages, in mice treated with transverse aorta constriction. Capsazepine also reduced expression of ornithine decarboxylase and cardiac polyamine levels. Transverse aorta constriction induced increases in phosphorylated calmodulin-dependent protein kinase IIδ and extracellular signal-regulated kinases, and p38 and Serca2a were attenuated by capsazepine treatment.. This study revealed that the mitogen-activated protein kinase signaling pathway and intracellular polyamines are essential for TRPV1 activation-induced cardiac hypertrophy.

Topics: Analysis of Variance; Animals; Aorta, Thoracic; Arachidonic Acids; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Capsaicin; Cardiomegaly; Cardiotonic Agents; Cells, Cultured; Down-Regulation; Endocannabinoids; Enzyme Inhibitors; Ligation; Male; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Myocytes, Cardiac; Polyamines; Polyunsaturated Alkamides; Rats, Wistar; RNA, Small Interfering; Signal Transduction; TRPV Cation Channels

: 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.

Topics: AMP-Activated Protein Kinases; Animals; Animals, Newborn; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoids; Cardiomegaly; Cardiotonic Agents; Endocannabinoids; Endothelin-1; Gene Knockdown Techniques; Ligands; Male; Myocytes, Cardiac; Naphthalenes; Nitric Oxide Synthase Type III; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Signal Transduction