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 8

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(a) TAC led to a substantial increase in systolic blood pressure (SBP) p...
(a) TAC led to a substantial increase in systolic blood pressure (SBP) proximal to the stenosis. SBP was significantly lower in the CM GC-A KO than in the floxed GC-A mice. For reference, pressures in sham-operated mice averaged 100 ± 6 mmHg (floxed GC-A) and 93 ± 10 mmHg (CM GC-A KO), indicating that a substantial pressure load was induced by TAC in both genotypes. (b) Despite the lower SBP, the CM GC-A KO mice had an increased LVW/BW index compared with the floxed GC-A mice. (c) The linear regression of SBP and LVW/BW index revealed that in the CM GC-A KO mice (filled circles and solid line), a stronger hypertrophic response in the heart correlated with lower blood pressures, while in the floxed GC-A mice (open circles and dashed line), blood pressure and LVW/BW index were positively correlated. (d) To compare the hypertrophic response independently of the differences in blood pressure in this figure, we divided the LVW/BW index of each animal by the individual SBP and normalized this value to the mean SBP of 145 mmHg (n = 18 floxed GC-A and 27 CM GC-A KO mice, *P < 0.05 vs. floxed GC-A).