Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A

Abstract

Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Atrial natriuretic peptide (ANP) has been postulated to exert local antihypertrophic effects in the heart. Thus, a loss of function of the ANP receptor guanylyl cyclase-A (GC-A) might contribute to the increased propensity to cardiac hypertrophy, although a causative role in vivo has not been definitively demonstrated. To test whether local ANP modulates cardiomyocyte growth, we inactivated the GC-A gene selectively in cardiomyocytes by homologous loxP/Cre-mediated recombination. Thereby we have circumvented the systemic, hypertensive phenotype associated with germline inactivation of GC-A. Mice with cardiomyocyte-restricted GC-A deletion exhibited mild cardiac hypertrophy, markedly increased mRNA expression of cardiac hypertrophy markers such as ANP (fivefold), α-skeletal actin (1.7-fold), and β-myosin heavy chain (twofold), and increased systemic circulating ANP levels. Their blood pressure was 7-10 mmHg below normal, probably because of the elevated systemic levels and endocrine actions of ANP. Furthermore, cardiac hypertrophic responses to aortic constriction were enhanced and accompanied by marked deterioration of cardiac function. This phenotype is consistent with a local function of the ANP/GC-A system to moderate the molecular program of cardiac hypertrophy.

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

“…The cardiomyocyte-restricted type A natriuretic peptide receptor-knockout mice show increases in LVH at baseline that are independent of blood pressure. 7 In this model, the disparities in cardiac hypertrophy were significantly increased on exposure to pressure overload introduced by aortic banding. More recently, cardiac-specific attenuation of the activity of type A natriuretic peptide receptor in transgenic mice with a cardiomyocyte-restricted expression of a dominant-negative mutation results in increased LVH and fibrosis, as well as increased mortality in response to pressure overload.…”

“…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. 7 Corin is a type II transmembrane serine protease recently demonstrated to be the "pro-A-type naturetic peptide/pro-B-type naturetic peptide convertase" that uniquely processes the natriuretic peptide precursor molecules into biologically active molecules. 8,9 We demonstrated recently that a minor allele in the human corin gene, defined by the presence of 2 single nucleotide polymorphisms (T555I and Q568) in near complete linkage disequilibrium, was enriched in black subjects and associated with higher blood pressure and an increased risk for prevalent hypertension.…”

Convergence of Protein Kinase C and JAK-STAT Signaling on Transcription Factor GATA-4

“…This may reflect a more specific role for the MAPK pathway in the growth (hypertrophic) effects of AII that are dependent on the EGF receptor (74). In contrast, ANF is a cardioprotective hormone that antagonizes cardiac hypertrophy (30). ANF is also a well-known antagonist of AII (39).…”

Ventricular Arterial Stiffening

“…Similarly, increasing cGMP/PKG activation in the heart reduces fibrosis and can be anti-hypertrophic. 57,58 In mice, PDE5a inhibition markedly inhibits the development of cardiac hypertrophy and fibrosis while improving ventricular function despite sustained ventricular afterload increase 59 (Figure 5B). Furthermore, this treatment reversed hypertrophy and fibrosis once established ( Figure 5C).…”