Abstract 19494: PGC-1α Mediates Anti-Remodeling Impact of cGMP-PDE5 Inhibitor in Failing Hearts

Abstract

Background: The transcriptional coactivator peroxisome proliferator-activated receptor- coactivator 1 (PGC-1α) is a master regulator of mitochondrial biology, regulating cardiac mitochondrial metabolism and oxidative stress, and its down-regulation has been implicated to play a key role in pathogenesis of heart failure. NO-cGMP signal reportedly up-regulates PGC-1α in adipose tissue. We hypothesize that cGMP signal activation by sildenafil (SIL) up-regulates PGC-1α in cardiac myocytes and ameliorates cardiac failure remodeling. Methods and Results: Neonatal rat ventricular myocytes (NRVM) exposed to phenylephrine (20µM 96hr) revealed ∼40% down-regulation of PGC1α and impaired mitochondrial respiration (65% decrease in respiratory control ratio, RCR), both of which were normalized by SIL (1µM). Direct cGMP-PKG activation by adenoviral PKG overexpression in NRVM up-regulated PGC1α, and increased mitochondrial respiration (120% with glutamate/malate substrate), whereas enhanced mitochondrial respiratory function was abrogated when PGC1α was silenced. These suggest cGMP-PKG up-regulates PGC1α and modulate mitochondrial respiration in cardiac myocytes. We next tested in vivo role of this regulation using animals lacking in PGC1α (KO). In wild type controls (WT), pressure-overload (TAC) induced dilating remodeling at 1-2 wk, which further develops failure over 7wks, associated with ∼50% down-regulation of PGC-1α, reduced mitochondrial biogenesis and respiratory function (RCR), and increased oxidative stress. SIL treatment (100mg/kg/day 6wk) up-regulates PGC1a, and improves all of these features, including RCR for all three substrates. In contrast, KO hearts developed significantly worse remodeling after 3wk of pressure-overload induction (%FS, WT-TAC: 41.08±7.50 vs. KO -TAC: 32.90 ± 12.08 at 3wk, WT-TAC: 34.30±7.51 vs. KO-TAC:19.90 ± 1.84 at 7wk). Importantly, 6wk Sil treatment did not have any impact on this late remodeling progression or mitochondrial respiratory function in KO hearts. Conclusion: Sildenafil reverses cardiac failure remodeling process via a PGC-1α dependent mechanism. This highlights the beneficial actions of sildenafil for the treatment of heart failure.