Abstract 1068: Genetic Evidence for a Central Role of cGMP-Dependent Protein Kinase I Alpha in Regulating Cardiac Hypertrophy In Vivo
The nitric oxide-cGMP-dependent protein kinase pathway is a central regulator of cardiovascular physiology. Protein Kinase G I (PKGI), a principle mediator of this pathway, has been implicated as a negative regulator of cardiac hypertrophy, but the specific mechanisms involved are unknown. To test the hypothesis that PKGIα regulates cardiac hypertrophy, we characterized the cardiac phenotype of mice homozygous for a mutant form of PKGIα in which critical amino acids in the N-terminal leucine zipper (LZ) motif have been substituted to disrupt PKGIα LZ binding to specific downstream effector proteins. In the unstressed state, male PKG Iα leucine zipper mutant ( LZM) mice develop progressive LV hypertrophy compared with wild type (WT) littermates with LV mass/tibia length 12.3% greater at 30 weeks of age (p=0.05), and 27% greater at 60 weeks (p=0.001). Compared with WT littermates, the hearts of 30 week old PKGIα mutants are hypercontractile with decreased end systolic diameter (p=0.02) and increased fractional shortening on echocardiography (p=0.03). Invasive hemodynamics demonstrate that LZM mice also have increased LV systolic pressure (p=0.04), developed pressure (p=0.05), and LV dP/dt max (p=0.13). To evaluate the response to hemodynamic stress, cardiac hypertrophy was induced by transaortic constriction (TAC) in male WT and LZM mice. TAC resulted in early mortality in the LZM mice (60%) compared to the WT (19%) mice at 21 days post procedure (p=0.008), with evidence of accelerated LV hypertrophy in the mice that died early (LV mass/tibia length 9.8 mg/mm in the early LZM deaths vs 7.2 mg/mm in WT survivors, p<0.001). Additionally, the LZM early deaths had evidence of congestive heart failure with increased RV mass (RV mass/ tibia length 1.8 mg/mm in LZM early deaths vs 1.2 mg/mm in WT survivors, p<0.05), and increased lung mass (23.1 mg/mm LZM early deaths vs 12.5 mg/mm in WT survivors, p<0.005). These findings support that the N-terminal LZ domain of PKGIα is required for suppression of cardiac hypertrophy. The early mortality following TAC in the LZM mice also suggests a critical role for PKGIα in attenuating pathologic cardiac remodeling, identifying PKGIα as an attractive candidate drug target for prevention of cardiac hypertrophy and failure.