Abstract 18932: Pka is a Master Regulator of Cardiac Hypertrophy Induced by Pressure Overload
Aims: Under pressure overload, the sympathetic nerve system is activated persistently leading to the overactivation of PKA. Conflicting roles of PKA in PCH have been reported. Also the roles of endogenous PKA inhibitor, PKI, in PCH have not been studied. This study aims to explore the role of PKI/PKA in PCH.
Methods and results: 1. RT PCR and Western blot showed that PKIα and PKIγ were highly expressed in the heart but only the expression of PKIα was reduced by transaortic banding (TAB); TAB induced a significant increases in cardiac PKA activity at 1 week post TAB; 2. An adenovirus containing PKI-GFP and 4 transgenic mouse lines overexpressing PKI-GFP were established. AdPKI-GFP (MOI=100) infection of neonatal ventricular myocytes (NRVMs) was able to completely inhibit PKA activation induced by cAMP in the extract . Two transgenic mouse lines with high (HE) and very low (VLE) expression of PKI-GFP that inhibited maximum PKA activity by 95% and 10% were used; overexpressed PKI-GFP does not inhibit the activity of other kinases; 3. In the VLE PKI-GFP TG hearts, the expression of PKI-GFP was mosaic and isolated GFP- LVMs (3224.6±83.4μm2, n=500, N=5) had significantly larger surface area than GFP+ LVMs (2135.6±127.0μm2, n=500, N=5); 4. TAB for 8 weeks did not change HW/BW (5.0±0.4 vs. 5.1±0.6mg/g BW), myocyte cross-sectional area (CSA: 721.2±25.4 vs. 754.1±37.8μm2), myocardial fibrosis (1.0 ±0.3% vs. 1.1±0.4%) and cardiac fractional shortening (FS: 41.4±2.1% vs. 40.8±1.9%) in PKI HE mice (TAB N=12 vs. Sham N=11) but induced significant increases in HW/BW (8.4±0.9 vs. 5.0±0.6mg/gBW), MCSA (1152.9±108.4 vs. 712.4±65.2μm2, ), myocardial fibrosis (12.5 ±1.6% vs. 0.8±0.1%) and depressed FS (38.4±2.4% vs. 24.1±3.1%) in control (TAB, N=8 vs. Sham, N=10; p<0.05) mice. 5. In cultured NRVMs, PKI-GFP prevented myocyte hypertrophy induced by isoproterenol (ISO), phenylephrine (PE) and angiotensin II, as evidenced by no significant increases in protein synthesis (protein/DNA ratio), myocyte surface area, sarcomere organization in AdPKI-GFP infected myocytes induced by these drugs; 6. PKI-GFP infection in NRVMs prevented the translocation of NFAT3 and HDAC5 induced by ISO and PE but increased ANF.
Conclusions: PKA is a master regulator of PCH induced by pressure overload.
- © 2013 by American Heart Association, Inc.