p38? MAPK contributes to left ventricular remodeling after pathologic stress and disinhibits calpain through phosphorylation of calpastatin.
p38? MAPK contributes to left ventricular remodeling after pathologic stress and disinhibits calpain through phosphorylation of calpastatin.
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p38？
DOI：
10.1096/fj.201701545r
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Loonat AA
中科院分区：
文献类型：
--
作者：
Loonat AA
尽管p38γ MAPK在心肌中高度且优先表达，但对其在心脏中的功能知之甚少。本研究的目的是阐明p38γ在心脏中的生理和生化作用。在小鼠心脏中测定p38亚型的表达和亚细胞定位。比较野生型和p38γ敲除（KO）小鼠在基线和腹主动脉结扎后的心脏功能和结构，证明KO小鼠发生的心室肥大较少，收缩功能得到更好的保护。为了鉴定p38γ的潜在底物，我们产生了类似物敏感的突变体来亲和标记内源性心肌蛋白。在其他蛋白质中，该技术将钙蛋白酶抑制蛋白鉴定为直接p38γ底物。此外，p38γ对钙蛋白酶抑制蛋白的磷酸化削弱了其抑制蛋白酶钙蛋白酶的能力。我们已经确定p38γ是小鼠主动脉缩窄后病理性心脏肥大进展的重要决定因素。此外，我们已经确定了钙蛋白酶抑制蛋白，以及其他底物，作为p38γ的新的直接靶点，可能有助于在p38γKO小鼠中观察到的保护作用。Loonat，A.一、Martin，E. D、Sarafraz-Shekary，N.，Tilgner，K.，Hertz，N. T.，莱文河，Shokat，K. M.，Burlingame，A. L.，Arabacilar，P.，Uddin，S.，托马斯，M.，Marber，M.美国，克拉克，J.E. p38γ MAPK参与病理性应激后的左心室重构，并通过磷酸化钙蛋白酶抑制剂（calpastatin）抑制钙蛋白酶。
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.