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Engineered Calcium Receptors in the Heart Improve Function

Researchers here demonstrate that using gene therapy to introduce a modified calcium receptor into the heart can improve the calcium signaling that drives the heartbeat, and that the effects are measurable even for a small uptake of the new receptor in heart cells. In the context of heart disease and degenerative aging of the heart, this approach could partially compensate for progressive failure of function in the organ, though it doesn't fix any of the underlying cell and tissue damage, or the prior remodeling of the heart caused by arterial stiffening and consequent hypertension.

Researchers have engineered new calcium receptors for the heart to tune the strength of the heartbeat in an animal model. The team developed a protein engineering approach by tailoring the heart's ability to respond to calcium, which is the signal for contraction. Using a modified version of troponin C (TnC L48Q), their study showed it can enhance or therapeutically preserve heart function and cardiovascular performance in mice without harmful effects commonly seen with other agents that increase heart muscle contraction.

Most heart muscle diseases involve problems with contraction. Many strategies increase the calcium signal to improve heart contraction. However, they do so at the expense of other functions. This can cause negative side effects, such as arrhythmias and cell death, and ultimately increase mortality. The team evaluated TnC L48Q in a common heart pathology - myocardial infarction, or a heart attack. Compared to the infarcted control group, TnC L48Q mice had better heart function and cardiovascular performance. There were also no signs of congestive heart failure or increased mortality, both of which were observed in the control group. When assessing the long-term effects and therapeutic potential of TnC L48Q, the researchers observed steady and significant improvement in heart function, cardiovascular performance, and significantly less detrimental remodeling compared to the control group. This resulted in better survival.

"It's long been presumed that altering the receptor would be ineffective, that it was better to change the calcium signal. We're seeing strong evidence that's not the case. Changing the calcium receptor does have a significant and safer impact." The scientists report these results were achieved by replacing only a modest amount of the original TnC receptor through gene therapy. This makes it more likely that this strategy will be a viable and personalized treatment option in the future. The researchers believe these findings could open the door for new treatments against cardiac diseases. In previous in vitro work, the team has customized several TnC receptors designed to combat various cardiac disorders. The team is also working on engineering other calcium receptors for a variety of diseases, such as high blood pressure and heart arrhythmias.

Link: http://wexnermedical.osu.edu/mediaroom/pressreleaselisting/tuning-calcium-receptors

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