MARK4 controls ischaemic heart failure through microtubule detyrosination.

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.

• Authors: 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, Xuan Li
• Journal: Nature (Nature) Vol. 594 Issue 7864 Pg. 560-565 (06 2021) ISSN: 1476-4687 [Electronic] England
• PMID: 34040253 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenic Proteins
• Microtubule-Associated Proteins
• VASH2 protein, mouse
• Tyrosine
• MARK4 protein, mouse
• Protein Serine-Threonine Kinases
• Carboxypeptidases
• tyrosyltubulin carboxypeptidase

Topics

• Angiogenic Proteins
• Animals
• Carboxypeptidases
• Cells, Cultured
• Heart Failure (physiopathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microtubule-Associated Proteins
• Microtubules (chemistry)
• Myocardial Infarction (physiopathology)
• Myocytes, Cardiac
• Protein Serine-Threonine Kinases (physiology)
• Stroke Volume
• Tyrosine (chemistry)
• Ventricular Function, Left