HomeScience and ResearchScientific ResearchThis Massive Myofibril Protein Gives Scientists a New Perspective on Heart Failure

This Massive Myofibril Protein Gives Scientists a New Perspective on Heart Failure

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When your heart is pounding and resting at its most efficient level, it reaches a specific level of stiffness.

Stresses such as age, hypertension, and obesity can cause the heart to stiffen up, preventing it from relaxing and filling with blood efficiently, resulting in diastolic dysfunction. In some cases, the heart isn’t rigid enough to pump efficiently, resulting in systolic dysfunction. Both disorders are potentially fatal.

Researchers at the University of Colorado School of Medicine have identified an enzyme that controls cardiac stiffness, paving the way for new heart failure medicines.

It’s been known for a while that HDAC6 has a role in heart disease and other conditions; however, new research by CU School of Medicine researchers Timothy McKinsey and Kathleen Woulfe shows that HDAC6 also plays a role in the regulation of myofibrils, the heart’s contractile units, which are regulated by HDAC6. The findings of the study were presented in an article today in The Journal of Clinical Investigation.

The function of titin

Researchers from the University of Colorado discovered evidence that HDAC6 acts on titin, a large myofibril protein that contributes to the stiffness of the heart. Tatin appears to lose its acetylation due to HDAC6’s action on the molecule. Inhibiting HDAC6 causes the heart to stiffen, while activating HDAC6 causes the heart to relax. HDAC6 enzyme activity or levels may be therapeutically adjusted to help the heart pump and relax at an optimal stiffness in the future, once cardiologists have determined which sort of malfunction a patient has.

“Heart failure is still a huge problem that affects millions of people worldwide,” say the authors. “Even though there are medications to treat heart failure, people with the condition still often have poor quality of life and die at an alarming rate. We think this discovery could provide a novel avenue for treating heart failure through a distinct mechanism.” 

The fact that HDAC6 inhibitors are being developed to treat other conditions, such as neurodegeneration and cancer, has aided the progress of therapeutically manipulating HDAC6 to treat heart failure, though McKinsey warns that people taking HDAC6 inhibitors should have their hearts monitored more closely.

“Our data suggest that in some cases, if you inhibit this enzyme, the heart might get too stiff,” write the authors. “Nevertheless, we firmly support continued clinical development of HDAC6 inhibitors, since this class of compounds holds great promise for treating a variety of devastating diseases, including certain forms of heart failure.”  

The study continues 

HDAC6 inhibitors will be tested in preclinical models of systolic cardiac failure where titin is too “compliant,” and gene therapy to supply active HDAC6 to hearts that are too stiff will be developed by the CU researchers. Much of their work is carried out in Woulfe’s lab, which is one of just a few in the world capable of isolating and studying myofibril mechanics.

“We are able to isolate proteins that direct contraction and relaxation in the heart in a way that preserves the mechanical function,” they say. “We can do this from tissue that’s frozen, from our human heart bank, or from animals. We take away everything else except for those proteins that contract and relax. They are the fundamental basis of the function of the heart. This system enabled us to discover that HDAC6 directly regulates myofibril stiffness, most likely by deacetylating titin.” 

“We think this is a major finding, and there’s still a lot more to do,” according to the authors. “Scientific discovery is a series of building blocks, and we believe this is a key building block that allows us to understand the mechanics of the heart better at a molecular level, and also suggests therapeutic potential. We’re going to keep vigorously working on the details of HDAC6 action in the heart.” 

Image Credit: Getty

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