Abstract
Treatment for heart disease, the leading cause of death in the world, has progressed little for several decades. Here we develop a protein engineering approach to directly tune in vivo cardiac contractility by tailoring the ability of the heart to respond to the Ca2+ signal. Promisingly, our smartly formulated Ca2+-sensitizing TnC (L48Q) enhances heart function without any adverse effects that are commonly observed with positive inotropes. In a myocardial infarction (MI) model of heart failure, expression of TnC L48Q before the MI preserves cardiac function and performance. Moreover, expression of TnC L48Q after the MI therapeutically enhances cardiac function and performance, without compromising survival. We demonstrate engineering TnC can specifically and precisely modulate cardiac contractility that when combined with gene therapy can be employed as a therapeutic strategy for heart disease.
Highlights
Treatment for heart disease, the leading cause of death in the world, has progressed little for several decades
We find that our Ca2 þ -sensitizing Troponin C (TnC) L48Q expressed before or after an myocardial infarction (MI), enhances heart function and performance without any adverse effects
Using high-content microscopy to analyse over 3,000 myocytes, we quantified that 70±3 percent of these myocytes were positive for mCherry fluorescence (Fig. 1f,g)
Summary
Treatment for heart disease, the leading cause of death in the world, has progressed little for several decades. Our smartly formulated Ca2 þ -sensitizing TnC (L48Q) enhances heart function without any adverse effects that are commonly observed with positive inotropes. We demonstrate engineering TnC can and precisely modulate cardiac contractility that when combined with gene therapy can be employed as a therapeutic strategy for heart disease. By applying the principles that govern Ca2 þ binding to TnC, we have smartly formulated TnC variants with a wide range of Ca2 þ sensitivities[5,6] These variants effectively modulate Ca2 þ sensitivity and force development from in silico to in vitro[5,7,8,9,10,11]. We find that our Ca2 þ -sensitizing TnC L48Q expressed before or after an MI, enhances heart function and performance without any adverse effects (that is, slow relaxation, arrhythmias or changing Ca2 þ ). Smartly formulating TnC combined with gene therapy is a powerful tool to develop unique and novel therapies with molecular precision to combat heart disease
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