MARK4 controls ischaemic heart failure through microtubule detyrosination

Xian Yu, Xiao Chen, Mamta Amrute-Nayak, Edward Allgeyer, Aite Zhao, Hannah Chenoweth, Marc Clement, James Harrison, Christian Doreth, George Sirinakis, Thomas Krieg, Huiyu Zhou, Hongda Huang, Kiyotaka Tokuraku, Daniel St Johnston, Ziad Mallat and Xuan Li ()
Additional contact information
Xian Yu: University of Cambridge, Addenbrooke’s Hospital
Xiao Chen: Huazhong University of Science and Technology
Mamta Amrute-Nayak: Hannover Medical School
Edward Allgeyer: University of Cambridge
Aite Zhao: Qingdao University
Hannah Chenoweth: University of Cambridge, Addenbrooke’s Hospital
Marc Clement: University of Cambridge, Addenbrooke’s Hospital
James Harrison: University of Cambridge, Addenbrooke’s Hospital
Christian Doreth: University of Cambridge, Addenbrooke’s Hospital
George Sirinakis: University of Cambridge
Thomas Krieg: University of Cambridge, Addenbrooke’s Hospital
Huiyu Zhou: University of Leicester
Hongda Huang: Southern University of Science and Technology
Kiyotaka Tokuraku: Muroran Institute of Technology
Daniel St Johnston: University of Cambridge
Ziad Mallat: University of Cambridge, Addenbrooke’s Hospital
Xuan Li: University of Cambridge, Addenbrooke’s Hospital

Nature, 2021, vol. 594, issue 7864, 560-565

Abstract: Abstract 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 rate1. 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 failure2,3 or have shown a very modest reduction of risk of heart failure4. Microtubule detyrosination is emerging as an important mechanism for the regulation of cardiomyocyte contractility5. 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.

Date: 2021
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DOI: 10.1038/s41586-021-03573-5

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