Abstract 3813: Guanylyl Cyclase-A Signaling Attenuates Salt Effect on Aldosterone-Induced Cardiac Remodeling
Background and Aim: Aldosterone (ALD) participates in hypertension and cardiac remodeling through mineralocorticoid receptor (MR) in salt excess but not normal salt condition. Mice lacking the gene encoding guanylyl cyclase-A/natriuretic peptide receptor (GC-A-KO) show hypertension and cardiac remodeling with normal dietary salt. We previously demonstrated that MR-signaling contribute to cardiac remodeling of GC-A-KO in normal dietary salt condition by using eplerenone, a specific MR blocker, in blood pressure (BP)-independent manner. However, the salt effect on ALD-induced cardiac remodeling is not fully understood. We investigated whether GC-A interacts with salt effect on ALD-induced cardiac remodeling (hypertrophy and fibrosis) with various dietary salt conditions in wild type mice (WT) and GC-A-KO.
Methods and Result: Male 12-weeks old WT and GC-A-KO were assigned to control and ALD-treatment group with low dietary salt (LS) (0.001% NaCl), normal dietary salt (NS) (0.6% NaCl) and high dietary salt (HS) (6.0% NaCl). Subpressor dose of exogenous ALD (100ng/kg/min) for 4 weeks significantly exacerbated cardiac remodeling in GC-A KO with NS and HS but not in GC-A KO with LS, and WT with any dietary salt conditions. ALD did not change BP in either WT or GC-A-KO in any salt conditions. The degree of ALD-induced cardiac remodeling in GC-A KO with HS was significantly higher than in GC-A KO with NS, in association with higher expression levels of mRNA of BNP and collagen I. These data clearly indicated that GC-A interact ALD-induced cardiac remodeling in BP-independent but salt-dependent manner. Furthermore HS without exogenous ALD-infusion tended to exacerbate cardiac remodeling in GC-A KO but not WT. There were no significant difference in plasma ALD levels and MR mRNA levels between WT and GC-A KO in each salt condition. These data probably indicated that disruption of GC-A acquired MR-hyperresponsiveness to ALD.
Conclusion: The present study demonstrates that exogenous ALD induces cardiac remodeling in GC-A KO even in the NS condition, but not in WT mice, indicating that the GC-A signaling attenuates salt effect on ALD-induced cardiac remodeling. GC-A probably also interacts ALD-induced MR-responsiveness in salt-dependent manner.