Brain MC4R-BAT-Heart crosstalk: a potential new therapeutic target for myocardial ischemia/reperfusion injury

PROJECT SUMMARY: Ischemic heart disease is the leading cause of death in U.S. and timely reperfusion of the occluded coronary artery after myocardial infarction (MI) is the most effective therapy currently available. However, additional ischemia/reperfusion (I/R) injury occurs in ~25% of patients who suffer MI and these patients often develop heart failure (HF). We recently demonstrated that activation of the brain leptin-melanocortin system pathway greatly improves cardiomyocyte energy metabolism and contractility, preserves cardiac function, and prevents progression of HF following I/R injury. Intracerebroventricular (ICV) infusion of leptin for 4 weeks, at a low dose that did not alter blood leptin concentration, improved cardiac function and metabolism after I/R injury. We also observed that these cardiac protective effects were absent in melanocortin 4 receptor (MC4R) deficient rats and that direct activation of brain MC4R using synthetic agonists (e.g. MTII), circumventing leptin signaling, also protected the heart from progressive cardiac dysfunction after MI. How the brain communicates with the heart during leptin-melanocortin system activation is still unknown. Our preliminary data suggest that the cardioprotective effect of ICV leptin or MTII infusion after I/R may be mediated by brown adipose tissue (BAT) since BAT surgical removal and BAT sympathectomy markedly attenuated the effects of central leptin or MTII administration to improve heart function post-I/R. Since obesity, a major cause of cardiovascular diseases, may induce leptin resistance, we will focus on activation of central MC4R pathway, bypassing leptin resistance. Therefore, we propose that activation of brain MC4R, via infusion of MTII directly into the brain, increases BAT activity through the sympathetic nervous system; once activated, BAT releases extracellular vesicles (EVs) containing cardioprotective microRNAs that reach the heart via the circulation and improve cardiac function and metabolism post-I/R. Our Research Strategy is organized in two aims. Aim 1 will test the hypothesis that BAT-derived EVs are essential for the cardioprotective actions of activating brain MC4R after cardiac I/R injury. Aim 2 will test the hypothesis that chronic activation of brain MC4R increases BAT-derived EVs that protect the heart from I/R injury by delivering cardioprotective microRNAs, including miR- 125b-5p. We will use state-of-the-art chronic in vivo protocols with high-resolution ultrasound techniques for imaging cardiac function in rats and mice combined with sophisticated molecular techniques for identification of the BAT-derived EVs cargo. Outcomes from this study could lead to novel and more effective therapeutic approaches for I/R and HF, and will provide a new target for MC4R agonists which are currently being used to treat rare forms of genetic obesity in humans.