Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A–deficient mice

Abstract

IntroductionThe natriuretic peptide system plays a crucial role in blood pressure (BP) and blood volume (BV) homeostasis. Increases in atrial stretch trigger the release of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which act through natriuretic peptide receptor A (NPRA) in the kidneys and vasculature to increase natriuresis, diuresis, and vasorelaxation (1-4).Elevations in circulating ANP and BNP are cardinal features of cardiac hypertrophy and heart failure in both humans and animal models (5-8), and induction of the ANP gene is one of the most robust responses to hypertrophic stimuli in the heart (9-12). Recent results suggest that these natriuretic peptides are not simply involved in BP and BV homeostasis but that they are also directly involved in moderating the cardiac growth response to hypertrophic stimuli. For example, the NPRA system has intrinsic growth inhibitory properties in noncardiac and cardiac cells in vitro (13). In endothelial and vascular smooth muscle cells (VSMCs), ANP is antimitogenic (14-17) and in cultured neonatal rat cardiomyocytes, ANP both attenuates the growth response to adrenergic stimuli (18) through a pathway that requires extracellular signal-related protein kinase (ERK) activation (19) and induces apoptosis (20). Furthermore, NPRA knockout mice (which have greatly attenuated responses to ANP and BNP) not only have increased BP, but also display marked cardiac hypertrophy and chamber dilatation by 3 months of age (21), whereas other mutant mice with similar increases in BP do not have this hypertrophic phenotype (22). These observations have led to the hypothesis that the NPRA signaling pathway plays an important autocrine role in the prevention of cardiac hypertrophy and heart failure beyond its effects on BP and BV regulation.To test the hypothesis that the NPRA pathway directly modulates the hypertrophic response we compare the response of Npr1 +/+ and Npr1 -/-mice to a pressure overload induced by transverse aortic constriction (TAC). We have also investigated the natural progression to cardiac hypertrophy that occurs in Npr1 -/-mice in the absence of TAC and the effects of chronic (3 months) BP normalization by enalapril, furosemide, hydralazine, or losartan. We conclude that the NPRA system indeed plays a primary role in moderating cardiac hypertrophy in vivo independently of its effects on BP regulation. Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber dilatation disproportionate to their increased blood pressure (BP), suggesting, in support of previous in vitro data, that the NPRA system moderates the cardiac response to hypertrophic stimuli. Here, we have followed the changes in cardiac function in response to altered mechanical load on the heart of NPRA-null mice (Npr1 -/-). Chronic treatment with either enalapril, furosemide, hydralazine, or losartan were all effective in reducing and maintaining BP at normal levels without affecting heart weight/body weight. In the reverse direction, we used t...

Beneficial Effects of Phosphodiesterase 5 Inhibition in Pulmonary Hypertension Are Influenced by Natriuretic Peptide Activity

“…Recent studies in NPR-A Ϫ/Ϫ mice suggest that NPR-A plays a greater role in inhibiting RV hypertrophy and pulmonary vascular remodeling than in inhibiting the rise in RVSP during chronic hypoxia 12 and that NPR-A inhibits cardiac hypertrophy independent of its effect on blood pressure and ventricular afterload. 13 Our data indicate that the natriuretic peptide-NPR-A pathway makes a greater contribution to the effect of sildenafil on RV hypertrophy and the muscularization of peripheral pulmonary vessels than its effect on RVSP in hypoxia-induced pulmonary hypertension.…”

“…Recent studies in NPR-A Ϫ/Ϫ mice suggest that NPR-A plays a greater role in inhibiting RV hypertrophy and pulmonary vascular remodeling than in inhibiting the rise in RVSP during chronic hypoxia 12 and that NPR-A inhibits cardiac hypertrophy independent of its effect on blood pressure and ventricular afterload. 13 Our data indicate that the natriuretic peptide-NPR-A pathway makes a greater contribution to the effect of sildenafil on RV hypertrophy and the muscularization of peripheral pulmonary vessels than its effect on RVSP in hypoxia-induced pulmonary hypertension.Exposure of the whole animal to hypoxia elevates endogenous ANP and BNP levels, which act through cyclic GMP to limit the rise in pulmonary vascular resistance and RV pressure load. 14 NPR-A-deficient mice are able to synthesize ANP and BNP but do not benefit from the elevated levels.…”

Cyclic Nucleotide Phosphodiesterase PDE1C1 in Human Cardiac Myocytes

“…The effects of PDE1 inhibition on cAMP content in intracellular compartments of cardiac myocytes are likely to differ from those of PDE3 inhibition, perhaps with more favorable sequelae. In animal models, inhibition of cGMP hydrolysis through PDE5 inhibition has been shown to prevent and reverse hypertrophic responses to pressure overload and ␤-adrenergic receptor stimulation and to reduce infarct area size and myocyte apoptosis in injured myocardium (51)(52)(53)(54)(55)(56)(57)(58)(59). PDE1 inhibition might elicit similar benefits.…”

Corin I555(P568) Allele Is Associated With Enhanced Cardiac Hypertrophic Response to Increased Systemic Afterload

“…T he natriuretic peptide system functions as an autocrine and paracrine hormonal system within the heart that opposes the development of cardiac hypertrophy by mechanisms that are independent from the ability of the natriuretic peptides to lower blood pressure. [1][2][3][4][5][6] For example, mice with cardiomyocyte-restricted inactivation of the natriuretic peptide receptor (natriuretic peptide receptor type-A) have a lower blood pressure than control mice (because of higher systemic A-type naturetic peptide levels because of loss of the negative feedback), but have increased ventricular hypertrophy at baseline. Moreover, the differences between the knockout and control mice in terms of cardiomyocyte hypertrophy and activation of the hypertrophic gene cascade were enhanced after the application of pressure overload induced by aortic banding.…”