Researchers at University of Colorado College of Medicine They discovered an enzyme that regulates heart stiffness, paving the way for the development of new treatments for heart failure.
Histone deacetylase 6 (HDAC6) has been studied in the context of many diseases, including heart disease, but CU Medical School researchers Timothy MackenziePh.D., Professor of Medicine at Cardiology DepartmentAnd Kathleen Wolf, Ph.D., assistant professor of medicine in the division of cardiology, recently discovered a new role for HDAC6 in regulating myofibrils, the contractile units of the heart. The research was published on May 16 in Journal of Clinical Investigation.
“When your heart is optimally pumping and relaxing, it is at a certain stiffness,” MacKenzie says. “Stress – including old age, high blood pressure and obesity – can cause severe heart stiffness, prevent it from relaxing and filling with blood efficiently, This leads to the so-called diastolic weakness. In other cases, the heart is not stiff enough, so it cannot pump blood effectively, resulting in systolic dysfunction. Both conditions are life-threatening.”
University of California researchers have found evidence that HDAC6 acts on titin, a massive muscle fibrous protein that contributes to hardening of the heart. HDAC6 appears to remove a chemical modification known as acetylation from titin. When HDAC6 is inhibited, titin causes the heart to become stiffer; When HDAC6 is activated, the heart becomes less stiff. In the future, once cardiologists determine what type of dysfunction a patient has, it may be possible to therapeutically modify the activity or enzymatic levels of HDAC6 to help the heart pump and relax to an optimal stiffness.
“Heart failure remains a huge problem that affects millions of people worldwide,” says McKenzie. Although there are medications to treat heart failure, people with this condition often still have a poor quality of life and die at an alarming rate. We believe this discovery could provide a new avenue for treating heart failure through a distinct mechanism.”
Advances in the therapeutic treatment of HDAC6 to treat heart failure are helped by the fact that HDAC6 inhibitors are being actively developed to treat other conditions, including neurodegeneration and cancer, although McKinsey cautions that the heart needs to be monitored more carefully in people receiving HDAC6 inhibitors.
“Our data suggest that in some cases, if you inhibit this enzyme, the heart can become overly rigid,” MacKenzie says. “However, we strongly support the continued clinical development of HDAC6 inhibitors, as this class of compounds holds great promise for treating a variety of diseases.” devastating, including some forms of heart failure.”
The search continues
The UCSD researchers plan to further study the role of HDAC6 in heart stiffness, including testing HDAC6 inhibitors in preclinical models of systolic heart failure where titin is highly “compatible”, and developing a gene therapy to provide activated HDAC6 to very stiff hearts. Much of their work is conducted in Wolff’s Laboratory, one of the few laboratories in the world that can isolate and study the mechanics of myofibrils.
“We are able to isolate the proteins that direct the contraction and relaxation of the heart in a way that preserves mechanical function,” says Wolf. We can do this from frozen tissue, from a human heart bank, or from animals. We take out everything else except those proteins that contract and relax. They are the basic basis of heart function. This system enabled us to discover that HDAC6 directly regulates myofibrillar stiffness, likely via titin deacetylation. ”
“We think this is an important discovery, and there is still a lot to do,” MacKenzie adds. “The scientific discovery is a series of building blocks, and we believe this is a key building block that allows us to better understand the mechanisms of the heart at the molecular level, and also suggests therapeutic potential. We will continue to actively work on the details of HDAC6’s action in the heart.”
This work was partially supported by consortium for fibrosis and translation research, a program funded by the CU College of Medicine and co-administered by McKinsey. It aims to improve the understanding of fibrotic diseases across different organ systems.
In addition to Woulfe and McKinsey, other researchers in the study are Ying-Hsi Lin, Jennifer Major, Joshua Travers, Sara Wennersten, Cortney Wilson, Korey Haefner, Maria Cavasin, Mark Jeong, Yu Han, Amrut Ambardekar, and Maggie Lam from CU School of Medicine Cardiology department; Scott Ferguson of the Cardiovascular and Lung Research Laboratory in the University of California Department of Medicine. Tim Lipner and Chunaram Choudary of the University of Copenhagen, Denmark; Zainab Hourani and Henk Granzier of the University of Arizona. and Michael Gotthardt of the Max Delbrück Center for Molecular Medicine in Germany.