| Background and Objective:Angiotensin Ⅱ (Ang Ⅱ) has been proven to promote cardiomyocyte hypertrophy. Apelin and its cognate G protein-coupled receptor APJ constitute a signaling pathway with a vasodepressor function in the systemic circulation. The apelin-APJ pathway appears to have opposing physiological roles to the renin-angiotensin system. This study investigated the effects of apelin on Ang II-dependent cardiomyocyte hypertrophy.Methods:Neonatal rat cardiomyocytes were prepared from2-day-old neonatal SD rats. Cardiomyocytes were randomly divided into eight groups according to the different incubation concentrations of apelin and Ang II.[3H]Leucine incorporation, cardiomyocyte surface area analysis and the whole protein content were measured to estimate cardiomycyte hypertrophy. Intracellular resting free calcium was tested by laser confocal scanning analysis. The protein expression levels of BNP, P-MHC, nuclear factor3of activated T cells (NFATc3), calcineurin, phospho-calcineurin, calmodulin kinase II (CaMKII) and phospho-CaMKII were assessed by Western blot analysis. RT-PCR was used to evaluate the mRNA level of BNP and p-MHC.Results:Apelin inhibited the hypertrophic response of cardiomyocytes to Arig II in a dose-dependent manner. These effects were concomitant to the decrease in Ang-II induced up-regulation of the level of resting intracellular free calcium, as well as the protein expression levels of phospho-calcineurin, NFATc3, CaMKII and phospho-CaMKII.Conclusion:Apelin behaves as a potent suppressor of AngⅡ-induced cardiac hypertrophy and this effect is possibly mediated by suppression of Ca2+-mediated calcineurin-NFAT and CaMKII signaling transduction pathways. Background and Objective:Hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death in the young, is characterized by cardiac hypertrophy and interstitial fibrosis. The cardiac troponin T (cTnT-Q92) transgenic mice, generated by cardiac-restricted expression of human HCM mutation, show a two-to three-fold increase in cardiac interstitial fibrosis. Angiotensin Ⅱ play an important role in the expression of phenotypes such as interstitial fibrosis in HCM. The objective was to determine whether apelin, a possible antagonist of angiotension Ⅱ, could reverse and attenuate cardiac interstitial fibrosis in the cTnT-Q92transgenic mouse model of human hypertrophic cardiomyopathy (HCM).Methods:We randomized16adult cardiac troponin T (cTnT-Q92) transgenic mice to treatment with apelin(0.1umol/kg/day) or placebo and included8nontransgenic mice as controls. The mean duration of therapy were8weeks.Results:There were no significant differences in the baseline characteristics of the groups. Mean age, number of males and females, and heart/body weight ratio were similar in the groups. We performed echocardiography before and after apelin treatment, followed by histologic and molecular characterization. Collagen volume fraction and extent of myocyte disarray were increased in the cTnT-Q92mice (placebo group) compared with nontransgenic mice (9.9±6.8%versus4.5±2.2%, P<0.01, and14.2±5.8%versus2.1±1.4%, P<0.01, respectively). The expression level of collagen1α1, smads2,3, and transforming growth factor-β1were reduced, and the expression level of smad7increased in immunohistochemical analysis, in which transforming growth factor-(31is a mediator of profibrotic effect, and smads2,3,7is the vital proteins in the transforming growth factor (31-dependent signaling transduction pathway. Westernblot and RT-PCR analysis revealed that the protein and mRNA expression level of collagen1α1,1α2,3α1, TGF-β1, smad2and smad3decreased obviously in the transgenic-apelin group in comparison with placebo group, whereas that of smad7was elevated in the transgenic-apelin mice compared with transgenic-placebo mice significantly.Conclusion:Treatment with apelin attenuated cardiac interstitial fibrosis via TGF-β1-dependent signaling transduction pathway in the hearts of cTnT-Q92transgenic mice. These findings suggest that apelin may have the potential to reverse or attenuate cardiac interstitial fibrosis in human patients with HCM. These findings suggest that apelin has the potential to reverse or attenuate interstitial fibrosis, a major predictor of sudden cardiac death, in human patients with HCM.
|
PDF Full Text Request