Aims: The role of PKA in pathological cardiac hypertrophy (PCH) is not clear. The literature suggests both prohypertrophic and antihypertrophic effects of PKA. Furthermore, there are endogenous PKA inhibitors, PKI, highly expressed in the heart to regulate PKA activity but their roles in PCH have not been studied. We aim to explore the role of PKI/PKA in PCH induced by isoproterenol, phenylephrine, angiotensin II and pressure overload.
Methods and Results: 1. PKIα and PKIγ were highly expressed in the heart but only PKIα was reduced by transaortic banding (TAB); TAB induced a significant increase in cardiac PKA activity at 1 week post TAB. 2. Four transgenic mouse lines with high (HE), medium (ME), low (LE) and very low (VLE) expression of PKI-GFP were obtained with the inhibition of maximum PKA activity induced by 1μM cAMP by 95%, 57%, 20% and 10% in the cardiac homogenates; 3. In the VLE hearts, some myocytes were PKI-GFP+ and some were PKI-GFP-, GFP- LVMs had significantly larger surface area than GFP+ LVMs; 4. PKA inhibition by PKI-GFP abolished PCH induced by isoproterenol, phenylephrine, angiotensin II in HE mice; 5. TAB for 8 weeks did not change HW/BW, myocyte cross-sectional area and myocardial fibrosis in HE mice but induced significant increases in HW/BW, myocyte cross-sectional area, myocardial fibrosis and depressed cardiac fractional shortening in control mice. 6. In cultured neonatal rat ventricular myocytes, 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. 7. PKI-GFP in NRVMs prevented the translocation of NFAT3 and HDAC5 induced by ISO and PE and increased the secretion of antihypertrophic ANF at baseline; 8. TAB induced PKA-dependent phosphorylation of GSK-3α and GSK-3β, inactivating them to relieve their antihypertrophic effect and promote protein synthesis (increased phosphorylation of mTORC1, eIF-4EBP1, p70 S6K); PKA inhibition abolished these effects.
Conclusions: PKA is regulated by PKI and is a master regulator of PCH induced by pressure overload.