Abstract 69: Requirement of Rac1 in Pressure Overload-induced Cardiac Remodeling, and Role of Mineralocorticoid Receptor as a Downstream Pathway

Abstract

A Rho family GTPase, Rac1, has emerged as an important molecule involved in cardiac remodeling. Some studies demonstrated the requirement of Rac1 in angiotensin II-induced cardiac hypertrophy and diabetic cardiomyopathy in association with generation of reactive oxygen species (ROS). However its role in pressure overload-induced cardiac remodeling is still unclear. On the other hand, we previously reported that Rac1 can activate mineralocorticoid receptor (MR) in cultured cardiomyocytes. Here we demonstrate the requirement of Rac1 in pressure-overload cardiac remodeling, and putative role of MR as a downstream pathway of Rac1. First, we performed sham or transverse aortic constriction (TAC) surgery in C57BL/6 mice, and examined the effect of Rac1 inhibitor ( NSC23766 ) and MR blocker (eplerenone). After 7 weeks, TAC caused severe hypertrophy and dysfunction of left ventricle with significant increase in active form of Rac1. In addition, the amount of MR protein in nuclear fraction, and the expression of some target genes of MR (including serpina3n and serpine-1) in left ventricle were also increased by TAC. NSC23766 significantly reduced the TAC-induced activation of Rac1, and both NSC23766 and eplerenone attenuated cardiac hypertrophy and dysfunction, along with inhibition of MR signaling. Furthermore, TAC significantly increased ROS production in left ventricle, which was also attenuated by both of the pharmacological interventions. We next generated cardiomyocyte-specific heterozygous Rac1-deficient mice (Rac1 CM +/− ) and littermate wild-type mice (WT), and performed Sham or TAC surgery. The TAC-induced hypertrophy and dysfunction of left ventricle were significantly suppressed in Rac1 CM +/− compared with WT (heart/body weight ratio: 6.4 ± 0.86 vs 10.8 ± 0.81 mg/g, ejection fraction 54.1 ± 6.5 vs 33.3 ± 7.3 %, p < 0.05), with inhibition of Rac1 activation. Nuclear translocation of MR protein and increases in expression of the target genes of MR were also significantly attenuated in Rac1 CM +/− compared with WT. These results indicate that Rac1 plays an essential role in the maladaptive cardiac hypertrophy induced by pressure overload, and that MR is an important downstream pathway of Rac1 in heart.