We are broadly interested in the role of cellular metabolism (or alterations in cellular metabolism) in regulating cardiac electrical and contractile function. Major ongoing projects include Cholesterol and KATP expression and Biochemical intermediates and cardiac function.
Our major research focus is the sarcolemmal ATP-sensitive (KATP) potassium ion channel which acts to protect the heart muscle during an ischemic episode or “heart attack”. We are investigating the molecular mechanisms that control expression of KATP channel subunits in the heart. These studies have led to the discovery that cholesterol is a key regulator of KATP expression. How cholesterol affects KATP channel expression and contributes to pathophysiology in patients with high cholesterol is the subject of further study. Ultimately, our goal is to identify pathways that might be exploited to modulate KATP channel density, to enhance the cardioprotective effects of KATP channels during ischemia and perhaps ameliorate the life-threatening arrhythmias that are associated with metabolic stress in the heart.
Our work recently led to the discovery that common biochemical intermediates such as acetate and lactate that are well known as oxidizable carbon sources used to form ATP in cells are also histone deacetylase inhibitors. Marked increases in plasma acetate and lactate are typically associated with heart healthy behaviors, like adherence to a high fiber diet and exercise. The finding that these biochemical intermediates are endogenous histone deacetylase inhibitors suggests a novel influence on gene expression and cardiac function through epigenetic mechanisms to modulate the penetrance of genetic variants associated with inherited cardiac diseases, like hypertrophic cardiomyopathy. Ongoing work on this project is exploring the effect of these common metabolites on gene expression and function in human induced pluripotent stem cell (iPSC) derived cardiomyocytes engineered to model hypertrophic cardiomyopathy.
Dr. Flagg Bio
USU Office of Research