MARK4 controls ischaemic heart failure through microtubule detyrosination
| Autor: | Thomas Krieg, Edward S. Allgeyer, Ziad Mallat, Daniel St Johnston, Mamta Amrute-Nayak, James Harrison, George Sirinakis, Xian Yu, Hannah L. Chenoweth, Kiyotaka Tokuraku, Huiyu Zhou, Christian Doreth, Marc Clement, Xiao Chen, Hongda Huang, Xuan Li, Aite Zhao |
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| Přispěvatelé: | Allgeyer, Edward [0000-0002-2187-4423], Sirinakis, George [0000-0002-4762-422X], Krieg, Thomas [0000-0002-5192-580X], Tokuraku, Kiyotaka [0000-0002-7747-4808], Johnston, Daniel St [0000-0001-5582-3301], Mallat, Ziad [0000-0003-0443-7878], Li, Xuan [0000-0002-0754-3011], Apollo - University of Cambridge Repository |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cardiac function curve Inotrope medicine.medical_specialty Myocardial Infarction Carboxypeptidases Protein Serine-Threonine Kinases 030204 cardiovascular system & hematology Microtubules Article Ventricular Function Left Contractility Mice 03 medical and health sciences 0302 clinical medicine Internal medicine Detyrosination Animals Medicine Myocytes Cardiac Myocardial infarction Angiogenic Proteins Cells Cultured Heart Failure Mice Knockout Multidisciplinary Ejection fraction biology business.industry Stroke Volume medicine.disease Mice Inbred C57BL 030104 developmental biology Tubulin Heart failure cardiovascular system biology.protein Cardiology Tyrosine business Microtubule-Associated Proteins |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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. MARK4 regulates cardiomyocyte contractility by promoting MAP4 phosphorylation, which facilitates the access of VASH2 to microtubules for the detyrosination of α-tubulin; MARK4 deficiency after acute myocardial infarction limits the reduction in the left ventricular ejection fraction. |
| Databáze: | OpenAIRE |
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