mdl-100907 and Constriction--Pathologic

Serotonin, in addition to its fundamental role as a neurotransmitter, plays a critical role in the cardiovascular system, where it is thought to be involved in the development of cardiac hypertrophy and failure. Indeed, we recently found that mice with deletion of monoamine oxidase A had enhanced levels of blood and cardiac 5-HT, which contributed to exacerbation of hypertrophy in a model of experimental pressure overload. 5-HT2A receptors are expressed in the heart and mediate a hypertrophic response to 5-HT in cardiac cells. However, their role in cardiac remodeling in vivo and the signaling pathways associated are not well understood. In the present study, we evaluated the effect of a selective 5-HT2A receptor antagonist, M100907, on the development of cardiac hypertrophy induced by transverse aortic constriction (TAC). Cardiac 5-HT2A receptor expression was transiently increased after TAC, and was recapitulated in cardiomyocytes, as observed with 5-HT2A in situ labeling by immunohistochemistry. Selective blockade of 5-HT2A receptors prevented the development of cardiac hypertrophy, as measured by echocardiography, cardiomyocyte area and heart weight-to-body weight ratio. Interestingly, activation of calmodulin kinase (CamKII), which is a core mechanism in cardiac hypertrophy, was reduced in cardiac samples from M100907-treated TAC mice compared to vehicle-treated mice. In addition, phosphorylation of histone deacetylase 4 (HDAC4), a downstream partner of CamKII was significantly diminished in M100907-treated TAC mice. Thus, our results show that selective blockade of 5-HT2A receptors has beneficial effect in the development of cardiac hypertrophy through inhibition of the CamKII/HDAC4 pathway.

Topics: Age Factors; Analysis of Variance; Animals; Aorta; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiomegaly; Constriction, Pathologic; Disease Models, Animal; Echocardiography; Fluorobenzenes; Gene Expression Regulation; Hemodynamics; Histone Deacetylases; Male; Mice; Mice, Inbred C57BL; Myocardium; Piperidines; Receptor, Serotonin, 5-HT2A; RNA, Messenger; Serotonin Antagonists

Serotonin via serotonin 2B receptors (SR2BR) regulates cardiac embryonic development and adult heart functions. However, the role of SR2BR in the failing heart due to pressure overload is not well understood.. Wistar rats of aortic banding and neonatal cardiomyocyte with mechanical stretch were used as cardiomyopathy models.. After two weeks of aortic banding surgery, serum serotonin, mRNA and protein expression of SR2BR increased significantly. The selective SR2BR antagonist, SB215505 (SB), significantly reduced the increase in heart weight, decreased heart wall thickness, left ventricular mass and the expression of the brain natriuretic peptide (BNP) but did not attenuate the up-regulation of SR2BR protein expression in rats after aortic banding for three weeks. After following in vitro mechanical stretch of cardiomyocytes and incubation with serotonin 1 muM, the level of SR2BR and BNP protein increased time-dependently. When transfected by specific siRNA of SR2BR or pretreated with caffeic acid phenethyl ester in cardiomyocytes, the increase of nuclear factor-kappaB (NF-kappaB) translocation and BNP protein induced by serotonin incubation plus mechanical stretch were both reversed.. SR2BR expression is involved in pressure-induced cardiomyopathy and its downstream signaling may involve NF-kappaB to modulate BNP expression in cardiomyocyte.

Topics: Animals; Animals, Newborn; Aorta; Caffeic Acids; Constriction, Pathologic; Heart Failure; Hypertrophy, Left Ventricular; Indoles; Models, Animal; Myocytes, Cardiac; Natriuretic Peptide, Brain; NF-kappa B; Phenylethyl Alcohol; Quinolines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2B; RNA Interference; RNA, Small Interfering; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Stress, Mechanical; Ventricular Remodeling