MARK4 controls ischaemic heart failure through microtubule detyrosination

Yu，Xian1; Chen，Xiao2; Amrute-Nayak，Mamta3; Allgeyer，Edward4,5; Zhao，Aite6; Chenoweth，Hannah1; Clement，Marc1; Harrison，James1; Doreth，Christian1; Sirinakis，George4,5; Krieg，Thomas7; Zhou，Huiyu8; Huang，Hongda9; Tokuraku，Kiyotaka10; Johnston，Daniel St4,5; Mallat，Ziad1,11; Li，Xuan1

2021

10.1038/s41586-021-03573-5

NATURE   影响因子和分区

0028-0836

1476-4687

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.

SCI

英语

NI论文

其他

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Multidisciplinary Sciences

WOS:000665247800019

NATURE RESEARCH

BIOLOGY & BIOCHEMISTRY;CLINICAL MEDICINE;MULTIDISCIPLINARY;PLANT & ANIMAL SCIENCE;ENVIRONMENT/ECOLOGY;SOCIAL SCIENCES, GENERAL;MICROBIOLOGY;ECONOMICS BUSINESS;IMMUNOLOGY;MATERIALS SCIENCE;COMPUTER SCIENCE;SPACE SCIENCE;MOLECULAR BIOLOGY & GENETICS;CHEMISTRY;NEUROSCIENCE & BEHAVIOR;PHYSICS;GEOSCIENCES;ENGINEERING

2-s2.0-85106460765

Scopus

1.Department of Medicine,Cardiovascular Division,University of Cambridge,Addenbrooke’s Hospital,Cambridge,United Kingdom
2.Department of Cardiology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China
3.Department of Molecular and Cell Physiology,Hannover Medical School,Hannover,Germany
4.The Gurdon Institute,University of Cambridge,Cambridge,United Kingdom
5.Department of Genetics,University of Cambridge,Cambridge,United Kingdom
6.College of Computer Science and Technology,Qingdao University,Shandong,China
7.Department of Medicine,Experimental Medicine and Immunotherapeutics Division,University of Cambridge,Addenbrooke’s Hospital,Cambridge,United Kingdom
8.School of Informatics,University of Leicester,Leicester,United Kingdom
9.Department of Biology,Southern University of Science and Technology,Shenzhen,China
10.Muroran Institute of Technology,Muroran,Japan
11.Université de Paris,Institut National de la Santé et de la Recherche Médicale,U970,PARCC,Paris,France

Yu，Xian,Chen，Xiao,Amrute-Nayak，Mamta,et al. MARK4 controls ischaemic heart failure through microtubule detyrosination[J]. NATURE,2021,594(7864).

Yu，Xian.,Chen，Xiao.,Amrute-Nayak，Mamta.,Allgeyer，Edward.,Zhao，Aite.,...&Li，Xuan.(2021).MARK4 controls ischaemic heart failure through microtubule detyrosination.NATURE,594(7864).

Yu，Xian,et al."MARK4 controls ischaemic heart failure through microtubule detyrosination".NATURE 594.7864(2021).