CGMP-PKG upregulates PGC1α and improves cardiac function in advanced cardiac hypertrophy independently of RGS2

Abstract

Results Impaired mitochondrial respiration was observed in advanced stage dilative 9wk TAC hearts, associated with down-regulation of PGC1a, but not in 1-3 wk TAC hearts. Delayed sildenafil treatment (100mg/kg/day) initiated after hypertrophy establishment (1-3 wk TAC) inhibited progression of remodeling up to 9wks, which was associated with restored PGC1a expression and preserved mitochondrial function, but not with RGS2 activation. Mice lacking RGS2 develop exacerbated early hypertrophy (1wk TAC) which is unresponsive to sildenafil, whereas sildenafil treatment initiated after 1wk ameliorated long term (up to 7wk) progression of cardiac remodeling and function, with restored PGC1a expression and improved mitochondrial respiratory function. Importantly, similar findings were obtained in PKG1a leucine zipper knock-in animals, wherein RGS2-PKG interaction is disrupted. In rat neonatal cardiac myocytes (RNCM), 72hr exposure to phenylephrine (Gq agonist, 20μM) down-regulated PGC1a and impaired mitochondrial respiration, both of which were normalized by sildenafil co-treatment (1μM). Over-expression of PKG up-regulated PGC1a in RNCM, increasing mitochondrial respiration, whereas this was not observed when PGC1a was silenced.