Mitogen-Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation-Induced Cardiac Hypertrophy

Background-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. Methods and Results-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 II delta and mitogen-activated protein kinases were found in TRPV1 agonist capsaicin-treated cardiomyocytes. Selective inhibitor of calmodulin-dependent protein kinase IId 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 II delta 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 II delta and extracellular signal-regulated kinases, and p38 and Serca2a were attenuated by capsazepine treatment. Conclusions-This study revealed that the mitogen-activated protein kinase signaling pathway and intracellular polyamines are essential for TRPV1 activation-induced cardiac hypertrophy.