Branched Chain Amino Acids and Heart Failure

项目总结

PROJECT SUMMARY Elevations of branched chain amino acids (BCAAs: leucine, valine, and isoleucine) in plasma are associated with, and may precede, the development of heart failure (HF). In mice, both supplementation of BCAAs and inhibition of whole-body BCAA catabolism worsen cardiac response to challenge. Conversely, promoting whole-body BCAA catabolism preserves cardiac contractility and reduces ventricular dilation in multiple models of HF. BCAA catabolism thus appears to benefit cardiac function. What is not known, however, is whether BCAA catabolism needs to occur in the heart or elsewhere in order to benefit cardiac function. In fact, it is unknown whether cardiac BCAA catabolism changes during HF pathogenesis. Based on my preliminary data, I hypothesize that: 1) the catabolism of BCAAs relative to other substrates is lower in failing than in non-failing hearts, but 2) it is the increase in peripheral BCAA catabolism that is critically needed to benefit cardiac function. To test these hypotheses, I will first compare the catabolism of BCAAs in the normal and failing heart. I will then manipulate tissue-specific BCAA catabolism to determine whether the protective effect of enhanced BCAA catabolism occurs by increasing BCAA breakdown in the heart or elsewhere. In my first aim, I will determine whether there are tissue-specific changes in the catabolism of BCAAs in murine models of heart failure. I will also extend these studies to humans by quantifying the transcardiac extraction of plasma BCAAs. I hypothesize that patients with heart failure will have a lower cardiac BCAA extraction ratio than those patients without failure. In the second part, I will test whether promoting BCAA catabolism in the skeletal muscle or the heart alone is sufficient to prevent heart failure. To do this, I will use tissue-specific deletion in mice of BCKDK, a key inhibitory kinase of the rate-limiting step of BCAA catabolism, in either the heart or the skeletal muscle and will assess the effects on baseline cardiac function and on its response to hemodynamic and ischemic challenges. I hypothesize that promoting BCAA catabolism in the skeletal muscle, but not in the heart, will protect cardiac function in the face of hemodynamic and ischemic challenges.