Research by the Medical Faculty of Charles University defines the role of HDAC6 in the regulation of cardiac stiffness

Research by the Medical Faculty of Charles University defines the role of HDAC6 in the regulation of cardiac stiffness

Researchers at the University of Colorado School of Medicine have discovered an enzyme that regulates heart stiffness and paved the way for the development of new treatments for heart failure.

The enzyme, histone deacetylase 6 (HDAC6), has been studied in connection with many diseases, including heart disease, but researchers at the UK School of Medicine Timothy McKinsey, PhD, Professor of Medicine in the Cardiology Division, and Kathleen Woulfe, PhD, Assistant Professor of Medicine in the Cardiology Division recently discovered a new role for HDAC6 in the regulation of myofibrils, the contractile units of the heart. The research was published on May 16 in The Journal of Clinical Investigation.

“When your heart pumps optimally and relaxes, it’s at a stiffness,” says McKinsey. “Stress – including aging, hypertension and obesity – can cause the heart to stiffen, prevents it from relaxing and filling itself with blood, which leads to what is called diastolic dysfunction. In other cases, the heart is not stiff enough so that it cannot pump efficiently, leading to systolic dysfunction. Both conditions are life-threatening. ”

The role of titin

Researchers in the UK have found evidence that HDAC6 acts on titanium, a massive myofibril protein that contributes to heart stiffness. HDAC6 appears to remove a chemical modification known as acetylation from titanium. When HDAC6 is inhibited, titin causes the heart to stiffen; when HDAC6 is activated, the heart becomes less stiff. In the future, once cardiologists determine what type of dysfunction the patient has, it may be possible to therapeutically adjust enzymatic activity or HDAC6 levels to help the heart pump and relax with optimal stiffness.

“Heart failure is still a big problem that affects millions of people around the world,” says McKinsey. “Even though there are drugs to treat heart failure, people with the disease still often have a poor quality of life and die at an alarming rate. We think this discovery could provide a new way to treat heart failure through a different mechanism.

Advances in the therapeutic manipulation of HDAC6 to treat heart failure are aided by the fact that HDAC6 inhibitors are being actively developed to treat other conditions, including neurodegeneration and cancer, although McKinsey warns that the heart should be monitored more closely in people taking HDAC6 inhibitors. .

“Our data suggests that in some cases, if you inhibit this enzyme, your heart may become too stiff,” says McKinsey. various devastating diseases, including certain forms of heart failure. ”

Research continues

Researchers in the UK plan to continue studying the role of HDAC6 in heart stiffness, including testing HDAC6 inhibitors in preclinical models of systolic heart failure where titin is too “flexible” and developing gene therapy to provide activated HDAC6 to hearts that are too stiff. Much of their work takes place in Woulfe’s laboratory, which is one of the few laboratories in the world that can isolate and study the mechanics of myofibrils.

“We are able to isolate proteins that control contraction and relaxation in the heart in a way that maintains mechanical function,” says Woulfe. “We can do it from frozen tissue, from our human heart bank, or from animals.” We take everything but the proteins that shrink and release. They are the basic basis of heart function. This system allowed us to determine that HDAC6 directly regulates myofibril stiffness, most likely by titanium deacetylation.

“We think it’s a crucial finding and there’s still a lot to do,” adds McKinsey. “Scientific discovery is a series of building blocks, and we believe that it is a key building block that allows us to better understand the mechanism of the heart at the molecular level and also suggests therapeutic potential. We will continue to work intensively on the details of HDAC6’s heartbeat. ”

This work was partially supported by Fibrosis Research and Translation Consortium, a program funded by the UK Medical School and co-directed by McKinsey. It aims to improve understanding of fibrotic diseases across different organ systems.

In addition to Woulfe and McKinsey, other researchers in the study include Ying-Hsi Lin, Jennifer Major, Joshua Travers, Sara Wennersten, Cortney Wilson, Korey Haefner, Maria Cavasin, Mark Jeong, Yu Han, Amrut Ambardekar and Maggie Lam of the Cardiology Department of the UK Medical School; Scott Ferguson of the Cardiovascular and Pulmonary Research Laboratory of the UK Medical Institute; Tim Liebner and Chunaram Choudhary of the University of Copenhagen, Denmark; Zaynab Hourani and Henk Granzier of the University of Arizona; and Michael Gotthardt of the Max Delbruck Center for Molecular Medicine in Germany.

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