Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression.

Abstract

IntroductionThe present study was aimed to test the role of endothelin-1 (ET-1) as a possible autocrine/paracrine growth factor for cardiac fibroblasts, and to examine its interaction with cardiac natriuretic hormones. Expression of preproET-1 (ppET-1) mRNA by cultured cardiac fibroblasts from neonatal rats was demonstrated by Northern blot analysis using cDNA for rat ppET-1 as a probe. Although cardiomyocytes occupy -75% of the structural space of the heart, they constitute only one third of the total cell population (1, 2). The remaining non-myocytes consist mainly of cardiac fibroblasts in the interstitium. It has been recently shown that growth of cardiac fibroblast associated with enhanced collagen accumulation in the myocardial interstitium is involved in the remodeling process of left ventricular hypertrophy (3, 4). Several recent in vivo studies have suggested that angiotensin II (ANG I) 1 is a critical growth factor for cardiac hypertrophy. Treatment with a subdepressor dose of angiotensin-converting enzyme inhibitors (5) and angiotensin receptor antagonists (6) prevent an increase in left ventricular mass. It has been also reported that chronic infusion of a subpressor dose of ANG II into rats causes left ventricular hypertrophy(6). Since ANG II stimulates cellular proliferation (7) and several extracellular matrix gene expressions in cardiac fibroblasts (8), and induces cardiomyocyte hypertrophy (9, 10), ANG II is considered to act directly on both cardiomyocytes and fibroblasts.We (11)

Quantitative analysis of the cardiac fibroblast transcriptome—implications for NO/cGMP signaling

“…Natriuretic peptides, NO, and cGMP-analogs have been shown to inhibit a number of important functions such as DNA synthesis and proliferation in cultured neonatal rat cardiac fibroblasts [32][33][34][35]. However the signalling pathway downstream of cGMP has not been clarified.…”

“…For proliferation assays, mouse cardiac fibroblasts (passage 15-20 as well as passage [27][28][29][30][31][32][33][34][35][36][37][38][39] were seeded onto 12 well plates (Greiner, Frickenhausen, Germany) at a density of 500 cells/cm 2 . Subconfluent cells were starved in medium containing 0.1 % FCS for 2 days, then cell proliferation was stimulated for 48 h by the addition of fresh medium containing 5 % FCS in the presence or absence of 8-pCPT-cGMP (Biolog, Bremen, Germany).…”

Cardiac fibrosis in mice lacking brain natriuretic peptide

“…These peptides are produced by cardiomyocytes and activate a common guanylyl cyclase-coupled natriuretic peptide receptor subtype, guanylyl cyclase-A (GC-A) that is expressed in a wide variety of tissues, thereby leading to an increase in intracellular cGMP concentrations (3)(4)(5)(6)(7)(8). It was also demonstrated that the natriuretic peptide͞cGMP system might antagonize the proliferation and extracellular matrix production of cardiac fibroblasts through the inhibition of renin-angiotensin and endothelin systems (2,9,10). Synthesis and secretion of ANP and BNP are markedly augmented in patients with congestive heart failure and animal models of ventricular hypertrophy (4-6, 11, 12).…”

Cardiac Endothelin System Impairs Left Ventricular Function in Renin-Dependent Hypertension via Decreased Sarcoplasmic Reticulum Ca 2+ Uptake

“…Local ET-1 production in the heart has been reported, with secretion from the endocardium, myocardium, and coronary endothelium 1,2 and from cardiac fibroblasts. 3 ET-1 is generated by the conversion of 2 precursors, preproET-1 and proET-1. In the heart, this conversion is controlled by ET-converting enzyme (ECE), the membrane-bound isoform of which is named ECE-1.…”