Relevance of brain natriuretic peptide in preload-dependent regulation of cardiac sarcoplasmic reticulum Ca2+ ATPase expression

Abstract

Background - In heart failure ( HF), ventricular myocardium expresses brain natriuretic peptide ( BNP). Despite the association of elevated serum levels with poor prognosis, BNP release is considered beneficial because of its antihypertrophic, vasodilating, and diuretic properties. However, there is evidence that BNP-mediated signaling may adversely influence cardiac remodeling, with further impairment of calcium homeostasis. Methods and Results - We studied the effects of BNP on preload-dependent myocardial sarcoplasmic reticulum Ca2+ ATPase ( SERCA2a) expression. In rabbit isolated muscle strips stretched to high preload and shortening isotonically over 6 hours, the SERCA/glyceraldehyde phosphate dehydrogenase mRNA ratio was enhanced by 168% ( n = 8) compared with unloaded preparations ( n = 8; P < 0.001). Recombinant human BNP at a concentration typically found in end-stage HF patients ( 350 pg/mL) abolished SERCA upregulation by stretch ( n = 9; P < 0.0001 versus BNP free). Inhibition of cyclic guanosine 3', 5' monophosphate ( cGMP)-phosphodiesterase-5 mimicked this effect, whereas inhibition of cGMP-dependent protein kinase restored preload-dependent SERCA upregulation in the presence of recombinant human BNP. Furthermore, in myocardium from human end-stage HF patients undergoing cardiac transplantation ( n = 15), BNP expression was inversely correlated with SERCA levels. Moreover, among 23 patients treated with left ventricular assist devices, significant SERCA2a recovery occurred in those downregulating BNP. Conclusions - Our data indicate that preload stimulates SERCA expression. BNP antagonizes this mechanism via guanylyl cyclase-A, cGMP, and cGMP-dependent protein kinase. This novel action of BNP to uncouple preload-dependent SERCA expression may adversely affect contractility in patients with HF.