p38γ MAPK contributes to left ventricular remodeling after pathologic stress and disinhibits calpain through phosphorylation of calpastatin

Despite the high and preferential expression of p38gMAPK in themyocardium, little is known about its function in the heart. The aimof the current studywas to elucidate the physiologic and biochemical roles of p38g in the heart. Expression and subcellular localization of p38 isoformswas determined inmouse hearts. Comparisons of the cardiac function and structure of wild-type and p38g knockout (KO)mice at baseline and after abdominal aortic banding demonstrated that KOmice developed less ventricular hypertrophy and that contractile function is better preserved. To identify potential substrates of p38g, we generated an analog-sensitive mutant to affinity tag en- dogenous myocardial proteins. Among other proteins, this technique identified calpastatin as a direct p38g sub- strate. Moreover, phosphorylation of calpastatin by p38g impaired its ability to inhibit the protease, calpain. We have identified p38g as an important determinant of the progression of pathologic cardiac hypertrophy after aortic banding inmice. In addition, wehave identified calpastatin, among other substrates, as a novel direct target of p38g thatmay contribute to the protectionobserved inp38gKOmice.—Loonat,A.A.,Martin,E.D., Sarafraz-Shekary,N., Tilgner, K., Hertz, N. T., Levin, R., Shokat, K.M., Burlingame, A. L., Arabacilar, P., Uddin, S., Thomas, M., Marber, M. S.,Clark,J. E. p38g MAPK contributes to left ventricular remodeling after pathologic stress and disinhibits calpain through phosphorylation of calpastatin.