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Yu, Xian; Chen, Xiao; Amrute-Nayak, Mamta; Allgeyer, Edward; Zhao, Aite; Chenoweth, Hannah; Clement, Marc; Harrison, James; Doreth, Christian; Sirinakis, George; Krieg, Thomas; Zhou, Huiyu; Huang, Hongda; Tokuraku, Kiyotaka; Johnston, Daniel St; Mallat, Ziad; Li, Xuan
Nature, 06/2021, Letnik: 594, Številka: 7864Journal Article
Myocardial infarction is a major cause of premature death in adults. Compromised cardiac function after myocardial infarction leads to chronic heart failure with systemic health complications and a high mortality rate . Effective therapeutic strategies are needed to improve the recovery of cardiac function after myocardial infarction. More specifically, there is a major unmet need for a new class of drugs that can improve cardiomyocyte contractility, because inotropic therapies that are currently available have been associated with high morbidity and mortality in patients with systolic heart failure or have shown a very modest reduction of risk of heart failure . Microtubule detyrosination is emerging as an important mechanism for the regulation of cardiomyocyte contractility . Here we show that deficiency of microtubule-affinity regulating kinase 4 (MARK4) substantially limits the reduction in the left ventricular ejection fraction after acute myocardial infarction in mice, without affecting infarct size or cardiac remodelling. Mechanistically, we provide evidence that MARK4 regulates cardiomyocyte contractility by promoting phosphorylation of microtubule-associated protein 4 (MAP4), which facilitates the access of vasohibin 2 (VASH2)-a tubulin carboxypeptidase-to microtubules for the detyrosination of α-tubulin. Our results show how the detyrosination of microtubules in cardiomyocytes is finely tuned by MARK4 to regulate cardiac inotropy, and identify MARK4 as a promising therapeutic target for improving cardiac function after myocardial infarction.
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in: SICRIS
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