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), alpha-skeletal actin (1.7-fold), and beta-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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 111 Issue 9 Pg. 1399-407 (May 2003) ISSN: 0021-9738 [Print] United States
• PMID: 12727932 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• RNA, Messenger
• Atrial Natriuretic Factor
• Myosin Heavy Chains
• Guanylate Cyclase
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor A

Topics

• Actins (genetics, metabolism)
• Animals
• Atrial Natriuretic Factor (genetics, metabolism)
• Blood Pressure (physiology)
• Body Weight
• Cardiomegaly (metabolism)
• Gene Deletion
• Guanylate Cyclase (genetics, metabolism)
• Hemodynamics
• Humans
• Mice
• Mice, Knockout
• Myocardial Contraction (physiology)
• Myocardium (cytology, metabolism)
• Myocytes, Cardiac (physiology)
• Myosin Heavy Chains (genetics, metabolism)
• Organ Size
• Phenotype
• RNA, Messenger (metabolism)
• Receptors, Atrial Natriuretic Factor (genetics, metabolism)