Systemic, but not cardiomyocyte-specific, deletion of the natriuretic peptide receptor guanylyl cyclase A increases cardiomyocyte number in neonatal mice.

Abstract

Guanylyl cyclase A (GC-A), the receptor for atrial and B-type natriuretic peptides, is implicated in the regulation of blood pressure and cardiac growth. We used design-based stereological methods to examine the effect of GC-A inactivation on cardiomyocyte volume, number and subcellular composition in postnatal mice at day P2. In mice with global, systemic GC-A deletion, the cardiomyocyte number was significantly increased, demonstrating that hyperplasia is the main cause for the increase in ventricle weight in these early postnatal animals. In contrast, conditional, cardiomyocyte-restricted inactivation of GC-A had no significant effect on ventricle weight or cardiomyocyte number. The mean volume of cardiomyocytes and the myocyte-related volumes of the four major cell organelles (myofibrils, mitochondria, nuclei and sarcoplasm) were similar between genotypes. Taken together, systemic GC-A deficiency induces cardiac enlargement based on a higher number of normally composed and sized cardiomyocytes early after birth, whereas cardiomyocyte-specific GC-A abrogation is not sufficient to induce cardiac enlargement and has no effect on number, size and composition of cardiomyocytes. We conclude that postnatal cardiac hyperplasia in mice with global GC-A inactivation is provoked by systemic alterations, e.g., arterial hypertension. Direct GC-A-mediated effects in cardiomyocytes seem not to be involved in the regulation of myocyte proliferation at this early stage.