Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A
Rita Holtwick, … , David L. Garbers, Michaela Kuhn
Rita Holtwick, … , David L. Garbers, Michaela Kuhn
Published May 1, 2003
Citation Information: J Clin Invest. 2003;111(9):1399-1407. https://doi.org/10.1172/JCI17061.
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Article Cardiology

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.

Authors

Rita Holtwick, Martin van Eickels, Boris V. Skryabin, Hideo A. Baba, Alexander Bubikat, Frank Begrow, Michael D. Schneider, David L. Garbers, Michaela Kuhn

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Figure 1

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Generation and Southern blot characterization of “flox/flox GC-A” and “f...
Generation and Southern blot characterization of “flox/flox GC-A” and “flox/flox GC-A × αMHC-Cretg” mice. (a) Restriction map of the targeting construct and the αMHC-Cre-generated deletion allele. B, BamHI site. (b) Southern blot analyses of genomic DNA obtained from tails, left ventricles, and enriched ventricular cardiomyocytes of “flox/flox GC-A” and “flox/flox GC-A × αMHC-Cretg” mice, demonstrating the deletion event that occurs in cardiomyocytes from mice harboring the αMHC-Cre transgene (CM GC-A KO mice). The Cre-mediated deletion event abolishes the additional BamHI site inserted in intron 1 by the recombination event. BamHI-digested DNA was hybridized with a specific cDNA probe (spanning E2–E6); 11-kb and 7.5-kb bands represent the deletion allele and targeted allele, respectively. (c) Efficiency of Cre-mediated GC-A deletion (n = 8).