Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B

Abstract

Natriuretic peptides (NP) mediate their effects by activating membrane-bound guanylyl cyclase-coupled receptors A (NPR-A) or B (NPR-B). Whereas the pathophysiological role of NPR-A has been widely studied, only limited knowledge on the cardiovascular function of NPR-B is available. In vitro studies suggest antiproliferative and antihypertrophic actions of the NPR-B ligand C-type NP (CNP). Because of the lack of a specific pharmacological inhibitor, these effects could not clearly be attributed to impaired NPR-B signaling. Recently, gene deletion revealed a predominant role of NPR-B in endochondral ossification and development of female reproductive organs. However, morphological abnormalities and premature death of NPR-B-deficient mice preclude detailed cardiovascular phenotyping. In the present study, a dominant-negative mutant (NPR-B⌬KC) was used to characterize CNP-dependent NPR-B signaling in vitro and in transgenic rats. Here we demonstrate that reduced CNP-but not atrial NP-dependent cGMP response attenuates antihypertrophic potency of CNP in vitro. In transgenic rats, NPR-B⌬KC expression selectively reduced NPR-B but not NPR-A signaling. NPR-B⌬KC transgenic rats display progressive, blood pressure-independent cardiac hypertrophy and elevated heart rate. The hypertrophic phenotype is further enhanced in chronic volume overload-induced congestive heart failure. Thus, this study provides evidence linking NPR-B signaling to the control of cardiac growth.C-type natriuretic peptide ͉ knockdown

Cardiomyocyte‐restricted over‐expression of C‐type natriuretic peptide prevents cardiac hypertrophy induced by myocardial infarction in mice

“…The prevention of hypertrophy by CNP over-expression in our transgenic mice that underwent myocardial infarction, agrees with data on the antihypertrophic effects of its receptor NPRB, as recently reported by Langenickel et al [27]. Transgenic rats expressing a dominant-negative mutant of NPRB (NPR-B ΔKC) developed progressive, blood pressure-independent cardiac hypertrophy [27].…”

“…Interestingly, there was no evidence for increased interstitial or perivascular fibrosis in these rats, supporting our finding of non-significant differences in the grade of stimulated fibrosis post-MI in CNP-transgenic mice compared to wild-type controls. Furthermore, chronic volume overload by an infrarenal aortocaval shunt in 8-week-old rats resulted in exaggerated cardiac hypertrophy in NPR-B ΔKC transgenic rats 6 weeks after surgery [27]. Although the affinity of CNP to NPRA is much less than to the NPRB receptor [28], and CNP does not increase cGMP accumulation in cells expressing human NPRA [11,29], we cannot finally exclude that transgenic CNP mediates part of its antihypertrophic effect via NPRA.…”

“…Transgenic rats expressing a dominant-negative mutant of NPRB (NPR-B ΔKC) developed progressive, blood pressure-independent cardiac hypertrophy [27]. Histological assessment and echocardiography revealed cardiac hypertrophy in these NPR-B ΔKC transgenic rats, which was aggravated with age accompanied by increasing cardiac markers of heart failure.…”

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events

“…Fibroblasts from NPRB‐deficient mice, however, showed blunted cGMP elevation in response to CNP stimulation 86. Overexpression of dominant‐negative NPRB in rats led to progressive cardiac hypertrophy that was not owing to elevation in blood pressure 87. On the other hand, continuous infusion of CNP for 2 weeks in rats with experimental MI significantly reduced both cardiac hypertrophy and fibrosis 88.…”

Visinin-like protein 1 regulates natriuretic peptide receptor B in the heart

“…They exert their biological actions by binding to cell surface receptors divided into particular guanylyl cyclase-coupled receptors NPR-A and -B and the clearance receptor NPR-C [15,16]. NPR-B has recently been shown to mediate antihypertrophic actions of its ligand C-type natriuretic peptide in vitro and in vivo thereby serving as potential pharmacological target for the treatment of cardiac hypertrophy and heart failure [17]. Only a few factors that are…”