Targeting Elastic Proteins as a Compensatory Therapy for Heart Failure

Researches here identify an interesting component of the detrimental changes that take place in heart tissue with age and dysfunction, leading to heart failure. Elastic proteins in the heart are produced in stiffer forms, leading to reduced function, and rebalancing the regulation of this system can improve the pumping of the failing heart. AS an intervention, this appears to be some way downstream from deeper causes, such as the accumulation of senescent cells in heart tissue. As is often the case, it is hard to draw a line of cause and effect leading from the fundamental underlying damage of aging to this alteration in the production of elastic proteins. Researchers tend to work backwards from the end state of an aged tissue, and stop at the first approach they find that might work, which is why most research does not lead to therapies that target root causes.

Patients with heart failure often have shortness of breath and become fatigued quickly. As people age the number of adverse factors increase, so heart failure primarily affects older people, especially women. Although the symptoms are similar, there are various causes. In one form of the condition the pumping function of the heart is impaired. This can however be improved with widely available medication. In the other form, the heart pumps with adequate force, but the chambers of the heart - the ventricles - fail to fill properly because the ventricular walls become thickened or stiff. There is currently no effective therapy for this form of heart failure.

The mechanics of the heart depend on an elastic giant protein called titin. It is produced by heart muscle cells in distinct variants or isoforms that differ in their flexibility. While very elastic titin proteins predominate in infants, later when growth and remodeling are completed, stiffer titin isoforms are produced to increase pumping efficiency. In heart failure with preserved ejection fraction, thickened heart walls, intercalated connective tissue, and stiffer titin filaments may lead to impaired filling of the ventricles.

"The mechanical properties of titin proteins are difficult to adjust. But we can now intervene in the process preceding protein synthesis - that is alternative splicing. Alternative splicing is a clever trick that nature has devised to create a variety of similar proteins based on a single gene - including the different forms of titin. This process is controlled by splicing factors. One of these, the master regulator RBM20, is a suitable target that we can address therapeutically."

Researcher have found a way to influence RBM20 with antisense oligonucleotides (ASOs). These are short chains of single-stranded nucleic acids that are synthetically produced. They bind specifically to the complementary RNA sequence, the blueprint of the targeted protein, thereby blocking its synthesis. Researchers successfully tested the ASOs in mice with stiffer heart walls. Researchers were able to stabilize the ASOs in such a way that they reach the striated muscles in the mouse model and are not already degraded in the blood, liver, or eliminated by the kidneys. Most of the therapeutic winds up in the heart, with some entering the skeletal muscle. Heart failure is a chronic disease that requires long-term treatment. "So we treated our mice over a longer period of time and were able to see lasting treatment effects."


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