Luke, I Am Your Daddy
All book sale proceeds and donations will help fund Restrictive Cardiomyopathy research.
Dr. Xupei Huang, M.D., Ph.D., associate professor of biomedical science in the Charles E. Schmidt College of Medicine, recently received funding from the National Institutes of Health (NIH) to further his project titled “Restrictive Cardiomyopathy Caused by Cardiac Troponin Mutations.”
Dr. Huang (standing) with Pierre-Yves Jean-Charles, a Ph.D. student and recipient of a pre-doctoral research fellowship from the American Physiological Society (2010-2012).
Restrictive cardiomyopathy is a disorder of the heart muscle in which the walls of the ventricles become stiff, and therefore resist normal filling of blood. Currently, there is no cure and few treatments are known to be effective. Huang’s investigation provides important clues on how a normal heart becomes abnormal, as well as how to prevent this rare, life-threatening condition, and develop optimal personalized treatments.
Among the key findings of their research, Huang and his team have found that in restrictive cardiomyopathy, calcium does not bind or properly drop off in the cardiac muscles and the muscle fibers have a hypersensitivity to the calcium. Therefore, traditional drug therapies such as calcium blockers do not work in restrictive cardiomyopathy. Huang is hoping to develop drugs that will reduce the calcium sensitivity and accelerate the calcium drop off from the protein in these diseased hearts.
This project was supported by the National Center for Research Resources and the National Heart, Lung and Blood Institute of the National Institutes of Health through grant number 1R15HL112130-01.
(http://fauf.fau.edu/news/?p=4480)
Abstract:
Cardiomyopathies are diseases that primarily affect the myocardium, leading to serious cardiac dysfunction and heart failure. Out of the three major categories of cardiomyopathies (hypertrophic, dilated and restrictive), restrictive cardiomyopathy (RCM) is less common and also the least studied. However, the prognosis for RCM is poor as some patients dying in their childhood. The molecular mechanisms behind the disease development and progression are not very clear and the treatment of RCM is very difficult and often ineffective. In this article, we reviewed the recent progress in RCM research from the clinical studies and the translational studies done on diseased transgenic animal models. This will help for a better understanding of the mechanisms underlying the etiology and development of RCM and for the design of better treatments for the disease.
Research
Abstract:
Heart muscle contraction is regulated by Ca2+ binding to the thin filament protein troponin C. In cardiovascular disease, the myofilament response to Ca2+ is often altered. Compounds that rectify this perturbation are of considerable interest as therapeutics. Plant flavonoids have been found to provide protection against a variety of human illnesses such as cancer, infection, and heart disease. (−)-Epigallocatechin gallate (EGCg), the prevalent flavonoid in green tea, modulates force generation in isolated guinea pig hearts (Hotta, Y., Huang, L., Muto, T., Yajima, M., Miyazeki, K., Ishikawa, N., Fukuzawa, Y., Wakida, Y., Tushima, H., Ando, H., and Nonogaki, T. (2006) Eur. J. Pharmacol. 552, 123–130) and in skinned cardiac muscle fibers (Liou, Y. M., Kuo, S. C., and Hsieh, S. R. (2008) Pflugers Arch.456, 787–800; and Tadano, N., Yumoto, F., Tanokura, M., Ohtsuki, I., and Morimoto, S. (2005) Biophys. J. 88, 314a). In this study we describe the solution structure of the Ca2+-saturated C-terminal domain of troponin C in complex with EGCg. Moreover, we show that EGCg forms a ternary complex with the C-terminal domain of troponin C and the anchoring region of troponin I. The structural evidence indicates that the binding site of EGCg on the C-terminal domain of troponin C is in the hydrophobic pocket in the absence of troponin I, akin to EMD 57033. Based on chemical shift mapping, the binding of EGCg to the C-terminal domain of troponin C in the presence of troponin I may be to a new site formed by the troponin C·troponin I complex. This interaction of EGCg with the C-terminal domain of troponin C·troponin I complex has not been shown with other cardiotonic molecules and illustrates the potential mechanism by which EGCg modulates heart contraction.