Abstract 12189: Cysteine Redox Dead in PKG-1α Suppresses Cardiac Pressure Overload-Induced Hypertrophy and Heart Failure
Introduction: Cyclic GMP-dependent protein kinase (PKG), specifically the 1α isoform, is recognized as redox-sensitive and potential antihypertrophic molecule. However, the mechanism by which oxidative stress-mediated PKG inhibits hypertrophic signaling remains to be clarified.
Hypothesis: We tested the hypothesis that the oxidation of cysteinyl thiols in PKG-1α isoform directly inactivates the kinase in heart and influences cardiac remodeling subjected to sustained pressure overload.
Methods: Pressure overload was produced by trans-aortic constriction (TAC) in wild-type or mutant PKG-1α mice with Serine substituted for Cysteine 42 (Cys42Ser). Echocardiography was performed weekly and animals were studied at 3 weeks after surgery.
Results: TAC significantly increased myocardial cGMP concentration in wild-type and Cys42Ser mutant PKG1α mice (p<0.01, respectively). TAC also remarkably and similarly increased the level of oxidized glutathione (GSSG) and decreased the ratio of reduced glutathione (GSH) to GSSG in both strains of mice (p<0.01, respectively). In contrast, TAC didn't change PKG activity at all in wild-type mice compared with sham controls. Then, TAC markedly caused the progression of left ventricular (LV) wall thickness (p<0.01), increased LV mass and LV weight (p<0.01), dilated LV diameter (p<0.05), and impaired cardiac systolic function (p<0.01) in wild-type mice. On the other hand, in Cys42Ser mutant mice TAC significantly increased PKG activity (p<0.01), which was measured by phosphorylation of threonine 68/119 residues on PKG substrate, and TAC-induced cardiac hypertrophy and heart failure were significantly prevented from the early stage compared with wild-type mice (p<0.05, respectively) despite the increase of oxidative stress. Thus, the oxidation-induced PKG-1α inactivation mediates cardiac pressure overload-stimulated hypertrophy and heart failure regardless of cGMP concentration.
Conclusions: The Cys42 redox sensor in PKG-1α alternatively enables to regulate the kinase in heart along with nitric oxide and cGMP. Redox-insensitive PKG-1α suppresses cardiac pressure overload-induced hypertrophy and heart failure.
- © 2011 by American Heart Association, Inc.