Installing Smartly Formulated Receptors Improves Function of Diseased Hearts

    A designer protein has been used to enhance cardiac contractility and alleviate heart disease, and the protein, a customized version of a Ca²⁺-sensitive receptor called Troponin C, is effective even if it is introduced in fairly modest degrees. The success of the customized Troponin C suggests that designer proteins, in combination with gene therapy, may be used to advance personalized medicine approaches in a range of diseases.

    Genes for modified Troponin C were transduced and expressed in a mouse model of myocardial infarction. This work, accomplished by scientists at Ohio State University, showed that receptors in the heart can be adjusted to respond more vigorously to Ca²⁺, which is the signal for contraction. Essentially, Ca²⁺receptors can be “tuned” so that they enhance or therapeutically preserve heart function and cardiovascular performance. Moreover, the approach appears to avoid the harmful effects commonly seen with other agents that increase heart muscle contraction.

    The Ohio State scientists, led by biophysicist Jonathan Davis, Ph.D., presented their results February 24 in the journal Nature Communications in an article entitled “Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease.” The article described how an old approach—increasing contractility—was revived in heart disease research through a new modality: protein engineering in combination with gene therapy.

    The old approach, which the scientists called “positive inotropy,” began to be seen as “whipping a sick horse to death.” Yet in the current study, positive inotropy was not observed to have any detrimental effects.

    “Transducing the myocardium with TnC L48Q increases cardiac function and performance without adversely affecting cardiac morphology, electrical activity, beta-adrenergic response, relaxation, diastolic function, intracellular Ca²⁺, or survival,” wrote the study’s authors. “Furthermore, TnC L48Q was not only protective but also therapeutic and beneficial chronically, unlike other positive inotropes.”

    Compared to an 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 and 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,” said Vikram Shettigar, lead author of the study. “Changing the calcium receptor does have a significant and safer impact.”

    “Positive effects can be achieved with only a modest replacement of the endogenous TnC, increasing the likelihood of gene therapy approaches for sarcomeric proteins,” the scientists noted in the Nature Communications article. “Since we did not observe any changes in cell death, fibrosis, or inflammation, we propose a new paradigm that smartly formulating TnC may be a viable therapeutic approach for many cardiomyopathies.”