Disruption of histamine H2 receptor slows heart failure progression through reducing myocardial apoptosis and fibrosis

Histamine H2receptor (H2R) blockade has been reported to be beneficial for chronic heart failure, but the mechanisms involved are not entirely clear.Here we assessed the influences of H2R disruption on the left ventricular (LV) dysfunction and the mechanisms involved in mitochondrial dysfunction and calcineurin-mediated myocardial fibrosis.H2R knockout mice and their wildtype littermates were subjected to transverse aortic constriction (TAC) or sham surgery. The influences of H2R activation or inactivation on mitochondrial function, apoptosis and fibrosis were evaluated in cultured neonatal rat cardiomyocytes and fibroblasts as well as murine hearts.Four weeks later, H2R knockout mice had a higher echocardiographic LV fractional shortening,a larger contractility index, a significantly lower LV end-diastolic pressure, and more importantly, a markedly lower pulmonary congestion, compared with the wildtype mice.Similar results were obtained in wildtype TAC mice treated with H2R blocker Famotidine. Histological examinations showed a lower degree of cardiac fibrosis and apoptosis in H2R knockout mice.H2R activation increased mitochondrial permeability and induced cell apoptosis in cultured cardiomyocytes, and also enhanced the protein expression of calcineurin, nuclear factor of activated T-cell and fibronectin in fibroblasts rather than in cardiomyocytes. These findings indicate that lack of H2R generates resistance towards heart failure and the process is associated with the inh...

Source: Clinical Science - March 21, 2014 Category: Biomedical Science Authors: Z Zeng, L Shen, X Li, T Luo, X Wei, J Zhang, S Cao, X Huang, Y Fukushima, J Bin, M Kitakaze, D Xu, Y Liao Source Type: research