UC San Diego

The serine/threonine kinase Akt is involved in many cellular processes including growth, survival, metabolism, protein synthesis, and angiogenesis. In particular, the activation of Akt induces cardiac hypertrophy, a process in which the heart undergoes cell enlargement in order to increase or maintain cardiac function. Akt activation causes physiological hypertrophy whereas prolonged Akt activation contributes to pathological hypertrophy and the development of heart failure. Extensive research has focused on regulating Akt activation; however, the mechanism of inactivation by phosphatases is largely unknown. A newly discovered phosphatase, PHLPP1 (PH domain leucine-rich repeat protein phosphatase) was found to dephosphorylate Akt. To determine the effect of PHLPP1 removal in the heart, we used global PHLPP1 knock-out (KO) mice. At baseline, wild-type (WT) and PHLPP1 KO exhibit no differences in heart size up to one year of age. However, PHLPP1 deletion increased Akt activity in the heart and cardiomyocytes. In a model for exercise-induced hypertrophy, loss of PHLPP1 resulted in increased heart size and myocyte cell area compared to WT. In contrast, in a model of pathological hypertrophy induced by transverse aortic constriction (TAC), compared to WT, PHLPP1 KO exhibited an attenuated increase in heart size, myocyte cell area, hypertrophic gene expression, fibrosis, and cell death. Furthermore, KO mice had a sustained increase in angiogenic marker expression and capillary density compared to WT. We demonstrate that removal of PHLPP1, which increases Akt activity in the heart to physiological levels without affecting cell size, increases angiogenesis and attenuates pathological hypertrophy following TAC