Switching off heart protein could protect against heart failure

A new way for drugs to combat heart failure in people who’ve had a heart attack.

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.

There is an unmet need to discover drugs that can effectively improve the heart’s capacity to pump blood proficiently after being damaged following a heart failure. Notwithstanding, numerous medications that make failing heart muscle contract more strongly have been considered perilous, leaving an immense hole in heart attack and heart failure treatment.

Scientists now believe that they might have identified a new drug target – a protein called MARK4.

Scientists from the University of Cambridge have identified elevated levels of MARK4 in mice after a heart attack. After comparing mice with and without MARK4 in the heart, they found that the absence of protein causes 57 percent better blood pumping.

This effect was observed after 24 hours after a heart attack and lasted for the entire follow-up period of four weeks.

This is the first time scientists discovered that MARK4 fine-tunes a structural network within the heart muscle cell – called the microtubule network. Increased MARK4 levels after a heart attack lead to tightly anchored microtubules onto the contractile machinery in the heart. This causes more onto the contractile machinery in the heart.

Decreased levels of MARK4 signifies loosely anchored microtubules. This makes it easier for the heart to contract and relax.

After a heart attack, in the heart muscle cells of mice without MARK4, the speed of contraction increased by 42 percent, and the speed of relaxation increased by 47 percent.

Scientists suggest that drugs to switch off MARK4 could provide a promising new way to improve recovery and help the heart pump blood more efficiently in people with failing hearts.

Dr. Xuan Li, BHF Intermediate Research Fellow at University of Cambridge BHF Centre of Research Excellence, said: “After years of research, we’ve revealed an entirely new and promising way that could help the recovery of failing hearts.”

“It’s early days, and we now need to test the longer-term effects of switching off MARK4. But if drugs to do that prove successful, the life-changing benefits could be seen in people with other types of heart disease as well as those who’ve had a heart attack and developed heart failure.”

Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation, said“Heart attacks are a significant cause of disability worldwide – people who’ve had a major heart attack are at much greater risk of developing chronic heart failure. Around 920,000 people live with heart failure in the UK, and we desperately need drugs to improve the heart’s function in these patients drastically.”

“These findings are a positive step forward. Further research is needed to refine and test drugs that can target MARK4 before we’ll see them given to people who’ve had a heart attack and develop heart failure.”

Journal Reference:
  1. Yu, X., Chen, X., Amrute-Nayak, M. et al. MARK4 controls ischaemic heart failure through microtubule detyrosination. Nature (2021). DOI: 10.1038/s41586-021-03573-5

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