Abstract 20875: cGMP-Dependent Protein Kinase I Alpha is Required for Suppression of Cardiac Remodeling and Controls Early JNK Activation in the Heart After Pressure Overload
Background: Protein Kinase G Iα has been implicated as a negative regulator of cardiac remodeling. Sildenafil (Sil), indirectly activates PKG by inhibiting PDE5 and raising cGMP levels. Sil suppresses remodeling induced by transaortic constriction (TAC). However, the specific role of PKG Iα, as opposed to other cGMP targets, in suppressing remodeling has not been explored. Therefore, we examined the TAC response of mice homozygous for a mutant form of PKGIα in which critical residues of the N-terminal leucine zipper motif were substituted to disrupt PKGIα binding to specific effectors. We used these PKG Iα Leucine Zipper Mutant (LZM) mice to test the hypothesis that PKG Iα inhibits TAC-induced cardiac remodeling in the setting of PDE 5 inhibition.
Results: WT and LZM male mice treated with 7 day sham or TAC received Sil 200 mg/kg/day or vehicle. In WT controls, TAC-induced increases in heart weight/ tibia length (HW/TL) (from 83.0 +/− 3.7 mg/cm in shams to 111.6 +/− 2.7 in vehicle treated TAC) were abolished by Sil (HW/TL 92.7 +/−5.9 in Sil treated TAC mice; p<0.05 Sil vs vehicle). TAC-induced decreases in fractional shortening percentage (FS%) (from 62.1 +/−1.4% in WT shams to 29.7+/−1.7% in WT TAC vehicle mice) were prevented by Sil (46.2 +/−5.1% in the WT TAC Sil group; p<0.05 Sil vs vehicle). In LZM mice, however, TAC-induced increases in HW/TL (increased from 71.3 +/−3.3 mg/cm in LZM shams to 115.7 +/−5.2 in the LZM TAC vehicle group) were not significantly reduced by Sil (105.5 +/− 5.1, p=ns LZM TAC Sil vs vehicle). There was no preservation of FS% in the LZM TAC Sil group, with a reduction in FS% from 62.6 +/− 0.6% in LZM shams to 20.2 +/−2.5% in the LZM TAC vehicle group, and a similar reduction to 19.3 +/− 2.8% in the LZM TAC Sil group (p=ns vehicle vs Sil). In response to 48 hour TAC, cardiac JNK phosphorylation was reduced from 3.4 +/− 1.4 densitometry units in the WT TAC group to 1.3 +/− 0.4 units in the LZM TAC group (p<0.001 WT TAC vs LZM TAC). Phosphorylation of the MAP Kinase Kinase MKK7 was also reduced in LZM compared with WT mice at 48 hours post TAC.
Conclusion: These findings provide direct evidence that PKG Iα is required for the suppression of cardiac remodeling, and identify JNK pathway activation as a potential novel mechanism of PKG Iα inhibition of remodeling in vivo.
- © 2010 by American Heart Association, Inc.