Abstract 17460: Sildenafil Upregulates Pgc1α and Mitochondrial Function in Advanced Cardiac Hypertrophy Independently of Rgs2 or Leucine-Zipper Function of Pkg1α
Enhanced cGMP-PKG signaling by PDE5 inhibitor, sildenafil (SIL), ameliorates cardiac mal-adaptive hypertrophy/remodeling. Although Gq inhibition via PKG-RGS2 activation is an essential mechanism for the early stage anti-hypertrophy under pressure-overload (TAC) in mice, the mechanism for the advanced disease stage remains unknown. Impaired mitochondrial respiration was observed in advanced stage dilative 9wk TAC hearts, associated with down-regulation of PGC1α and reduced mitochondrial biogenesis (mt cytochrome b/ b-actin DNA), but not in 1-3 wk TAC hearts. Delayed SIL treatment (100mg/kg/day) initiated after hypertrophy establishment (1-3 wk TAC) inhibited progression of remodeling up to 9wks, which was associated with restored PGC1α expression and preserved mitochondrial function, but not with RGS2 activation. RGS2 null (KO) mice or PKG1α leucine zipper mutant knock-in (LZM) mice harboring disrupted RGS2-PKG interaction develop exacerbated early hypertrophy (1wk TAC) which is unresponsive to SIL, whereas SIL initiated after 1wk ameliorated long term (up to 7wk) progression of cardiac remodeling and function, with restored PGC1α expression, mitochondrial biogenesis and improved mitochondrial respiration assessed in cardiac fibers when palmitoyl carnitine (state3 O2 consumption, nmol/min/mg dry fiber, RGS2KO TAC: SIL 13.52±1.68 vs veh 8.47±0.87; LZM TAC: SIL 14.04±1.06 vs veh 8.79±1.27) or glutamate/malate(RGS2KO TAC: SIL 18.69±2.78 vs veh 9.58±0.78; LZM TAC: SIL 15.81±1.66 vs veh 9.68±1.16) was used as substrate. In rat neonatal cardiac myocytes (RNCM), 72hr exposure to phenylephrine (Gq agonist, 20µM) down-regulated PGC1α and impaired mitochondrial respiration, both of which were normalized by SIL co-treatment (1µM). Over-expression of PKG up-regulated PGC1α in RNCM, increasing mitochondrial respiration, whereas this was not observed when PGC1α was silenced. These results suggest enhancing cGMP-PKG signaling by SIL improves cardiac energetics by restoring myocyte PGC1α and thereby ameliorates remodeling progression in advanced stage of pressure-overload hypertrophy, which is independently of RGS2 or LZ function of PKGIa.
- © 2011 by American Heart Association, Inc.