PROJECT SUMMARY/ABSTRACT Over the past years, research from around the globe has focused on the consumption of red meat and the risk of cardiovascular disease. This positive correlation has been linked to excess heme and its degradation product iron (Fe2+), which are abundant in red meat. Heme serves as a stable cofactor consisting of an iron (Fe2+) coordinated to a porphyrin-IX, often conferring gas sensitivity as exemplified in cytochromes, hemoglobin, myoglobin, and soluble guanylyl cyclase. Excess heme in the system is catabolized by heme oxygenase, which produces carbon monoxide (CO), iron and biliverdin. Emerging evidence, however, suggests a new paradigm of the heme function; intracellular free heme can act as a potent non-genomic acute signaling molecule capable of directly regulating ion channel proteins. Despite the probable physiological and pathophysiological role of heme and other hemp-derived molecules, our knowledge of the acute targets/effectors of heme signaling in the cardiovascular system is severely limited. The goal of this proposal is to define the impacts of heme and heme degradation products (CO) on cardiovascular function by addressing the following questions 1) How do heme and CO impact cardiac ion channels? 2) Does excess heme and CO alter mitophagy in cardiac cells?

PROJECT NARRATIVE Heme (iron protoporphyrin-IX) is traditionally viewed as a stable protein cofactor, often conferring gas sensitivity to many proteins. Emerging evidence, however, suggests a new paradigm of the heme function; intracellular free heme can act as a potent non-genomic acute signaling molecule capable of directly regulating ion channel proteins. The focus of the project proposed here is to elucidate the mechanisms of modulation of cardiac potassium channels by heme and carbon monoxide. This critical knowledge gap will advance our understanding of the newly uncovered acute intracellular signaling by free heme and heme-derived molecules in the cardiovascular system.