Abstract

Despite the high and preferential expression of p38γ MAPK in the myocardium, little is known about its function in the heart. The aim of the current study was to elucidate the physiologic and biochemical roles of p38γ in the heart. Expression and subcellular localization of p38 isoforms was determined in mouse hearts. Comparisons of the cardiac function and structure of wild-type and p38γ knockout (KO) mice at baseline and after abdominal aortic banding demonstrated that KO mice developed less ventricular hypertrophy and that contractile function is better preserved. To identify potential substrates of p38γ, we generated an analog-sensitive mutant to affinity tag endogenous myocardial proteins. Among other proteins, this technique identified calpastatin as a direct p38γ substrate. Moreover, phosphorylation of calpastatin by p38γ impaired its ability to inhibit the protease, calpain. We have identified p38γ as an important determinant of the progression of pathologic cardiac hypertrophy after aortic banding in mice. In addition, we have identified calpastatin, among other substrates, as a novel direct target of p38γ that may contribute to the protection observed in p38γKO mice.-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. p38γ MAPK contributes to left ventricular remodeling after pathologic stress and disinhibits calpain through phosphorylation of calpastatin.

Highlights

  • The current study provides experimental evidence for a putative role for p38g MAPK in the progression of cardiac hypertrophy and heart failure and elucidates a mechanism of action

  • Ejection fraction, fractional shortening, and endocardial fractional area of change were preserved in p38gKO mice at 5 wk after banding (Fig. 3A–C) and KO hearts exhibited significantly less left ventricle (LV) chamber dilatation and myocardial wall thickening compared with WT litter mates (Fig. 3D–F)

  • The purpose of the current study was to decipher the role played by p38g in the heart

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Summary

Introduction

The current study provides experimental evidence for a putative role for p38g MAPK in the progression of cardiac hypertrophy and heart failure and elucidates a mechanism of action. ABBREVIATIONS: AS, analog sensitive; CID, collision-induced dissociation; IPTG, isopropyl b-D-1-thiogalactopyranoside; KO, knockout; LC-MS/MS, liquid chromatography–tandem mass spectrometry; LV, left ventricle; NFAT, nuclear factor of activated T cell; PNBM, p-nitrobenzyl mesylate; WT, wild type; b-MHC, b-myosin heavy chain. The remaining 2 p38 MAPK isoforms are not inhibited by pyridynylimadazoles and exhibit differential expression patterns [2]. Given the differential localization of p38a and p38g in unstimulated cardiomyocytes and in

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