NHE-1 participates in isoproterenol-induced downregulation of SERCA2a and development of cardiac remodeling in rat hearts

Shibata M, Takeshita D, Obata K, Mitsuyama S, Ito H, Zhang G, Takaki M. NHE-1 participates in isoproterenol-induced down-regulation of SERCA2a and development of cardiac remodeling in rat hearts. Am J Physiol Heart Circ Physiol 301: H2154-H2160, 2011. First published August 19, 2011; doi:10.1152/ajpheart.00483.2011.Impaired Ca2+ handling is one of the main characteristics in heart failure patients. Recently, we reported abnormal expressions of Ca2+-handling proteins in isoproterenol (ISO)-induced hypertrophied rat hearts. On the other hand, Na+/H+ exchanger (NHE)-1 inhibitor has been demonstrated to exert beneficial effects in ischemic-reperfusion injury and in the development of cardiac remodeling. The aims of the present study are to investigate the role of NHE-1 on Ca2+-handling and development of cardiac hypertrophy in ISO-infused rats. Male Wistar rats were randomly divided into vehicle [control (CTL)] and ISO groups without or with pretreatment with a selective NHE-1 inhibitor, BIIB-723. ISO infusion for 1 wk significantly increased the ratios of heart to body weight and left ventricle (LV) to body weight and collagen accumulation. All of these increases were antagonized by coadministration with BIIB-723. The ISO-induced significant increase in LV wall thickness was suppressed significantly (P < 0.05) by BIIB-723. ISO-induced decreases in cardiac stroke volume and a total mechanical energy per beat index, systolic pressure-volume area at midrange LV volume, were normalized by BIIB-723. The markedly higher expression of NHE-1 protein in the ISO group than that in CTL group was suppressed (P < 0.05) by BIIB-723. Surprisingly, ISO induced downregulation of the important Ca2+-handling protein sarcoplasmic reticulum Ca2+-ATPase 2a, the expression of which was also normalized by BIIB-723 without changes in phosphorylated phospholamban (PLB)/PLB expression. We conclude that NHE-1 contributes to ISO-induced abnormal Ca2+ handling associated with cardiac hypertrophy. Inhibition of NHE-1 ameliorates cardiac Ca2+-handling impairment and preventsthe development of cardiac dysfunction in ISO-infused rats.