Abstract 16984: PI3K? Regulates Age-Dependent Cardiac Growth Through Inhibition of PP2A Mediated Dephosphorylation of GSK-3
Activation of phosphoinositide 3-kinase α (PI3Kα) by Receptor Tyrosine Kinase or PI3Kγ by G-protein coupled receptor inhibits glycogen synthase kinase-3 (GSK-3) via protein kinase B (Akt). Previously, we showed that in addition to promoting GSK-3 phosphorylation through Akt, PI3Kγ in parallel suppresses PP2A dependent GSK-3 dephosphorylation. Mechanistically, we found that elevated PP2A activity in PI3Kγ-KO was due to PP2A methylation mediated by elevated PP2A methyl transferase (PPMT-1) activity. Consistent with the elevated anti-hypertrophic GSK-3 activity, we observed reduced heart size in PI3Kγ-KO mice. To test in vivo whether PI3Kγ activity regulates cardiac growth, we bred transgenic mice with cardiac overexpression of inactive PI3Kγ (PI3Kγinact) and constitutively active PI3Kγ (myrPI3Kγ) with PI3Kγ-KO mice to generate mice with cardiac specific expression of PI3Kγinact (PI3Kγinact/KO) and myrPI3Kγ (myrPI3Kγ/KO). To assess the kinase independent role of PI3Kγ in regulating cardiac hypertrophic growth with age, we have carried out echocardiography on PI3Kγinact/KO, myrPI3Kγ/KO and their littermate controls. Surprisingly, we observed significant increase in cardiac morphometric measurements including increase in heart size for PI3Kγinact/KO (LVEDD- 3.41± 0.12) and myrPI3Kγ/KO (LVEDD- 3.73 ± 0.14) compared to their littermate controls (LVEDD- 3.00 ± 0.15) suggesting kinase independent regulation of cardiac growth with age. In addition to increase in heart size, these mice were characterized by cardiac dysfunction as measured by fractional shortening [% FS - 33.7 ± 6.5 (PI3Kγinact/KO), 36.3 ± 3.6 (myrPI3Kγ/KO)]. Our biochemical studies show that cardiac PPMT-1 activity was decreased resulting in reduced PP2A activity leading to increased GSK-3 phosphorylation. Increased GSK-3 phosphorylation inhibits anti-hypertrophic function of GSK-3 suggesting that kinase independent function of PI3Kγ overrides functional manifestation of its own kinase activity. Thus, our data on regulation of GSK-3 function downstream of PI3Kα and control of cardiac hypertrophic response by kinase independent function of PI3Kγ suggests a greater pivotal role for kinase independent function of PI3Kγ in cardiac hypertrophy observed with age.
- © 2013 by American Heart Association, Inc.