Relevance of Brain Natriuretic Peptide in Preload-Dependent Regulation of Cardiac Sarcoplasmic Reticulum Ca ²⁺ 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 Ca 2+ 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.

HDAC4 controls histone methylation in response to elevated cardiac load

“…Furthermore, mRNA expressions of α-myosin heavy chain (α-MHC; also known as MYH6) and sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a; also known as ATP2A2) were downregulated ( Figure 1, D and E), both of which are characteristic hallmarks of human heart failure (3)(4)(5). In agreement with a previous study (5), an inverse correlation was observed between BNP and SERCA2a expression ( Figure 1F). …”

“…Since no differences between ICM and DCM were detected in most subsequent analyses, unless indicated otherwise, these groups were merged into a single group referred to herein as failing myocardium. As described previously (3)(4)(5), ANP and BNP were upregulated in failing versus nonfailing myocardium, with a close correlation between both natriuretic peptides ( Figure 1, A-C). Furthermore, mRNA expressions of α-myosin heavy chain (α-MHC; also known as MYH6) and sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a; also known as ATP2A2) were downregulated ( Figure 1, D and E), both of which are characteristic hallmarks of human heart failure (3)(4)(5).…”

“…Deterioration of cardiac function during heart failure progression is associated with activation of genes that trigger structural, functional, and electrical remodeling of the heart. In particular, the reactivation of a set of fetal genes, including atrial natriuretic peptide (ANP; also known as Nppa) and brain natriuretic peptide (BNP; also known as Nppb), correlates well with the clinical severity and prognosis of the disease (3)(4)(5). The mechanisms that regulate the reactivation of this fetal gene program, however, are incompletely understood.…”

Mechanical load‐dependent cardiac ER stress in vitro and in vivo: Effects of preload and afterload

“…Induced downregulation of SERCA in transgenic mice led to an induction of ER stress [24]. We have previously shown that afterload-induced upregulation of BNP counteracts the preload-induced and calcineurin-mediated increase in the expression of SERCA2a [25][26][27]. This upregulation of SERCA2a by preload in the isotonic stretched muscles strips after 6 h might help to keep the intraluminal ER Ca 2+ concentration normal and might therefore protect the cells from ER stress.…”

Disease-Modifying Mutations in Familial Hypertrophic Cardiomyopathy

“…Because brain natriuretic peptide has also been found to be significantly upregulated in tni-203/mhc-403 mice and because it has been shown to downregulate serca2a expression, brain natriuretic peptide induction might be, at least in part, responsible for serca2a downregulation. 11 Brain natriuretic peptide gene expression itself depends on activity of the transcription factor nuclear factor of activated T cells. However, Tsoutsman et al 6 did not find evidence of the activated upstream signaling mechanisms of the nuclear factor of activated T cells, mainly mitogen activated protein kinases, in tni-203/mhc-403 mice.…”