Area #2: Examining the Role of Reactive Aldehydes on Cardiac Remodeling with Obesity and Aging
EJ Anderson Lab
Human gpx4 gene variants have been linked to obesity and cardiovascular diseases in recent studies. We are examining cardiac GPx4 levels and lipid peroxidation in human heart samples and in peripheral blood mononuclear cells (PBMCs) to determine if there is an association between these variables and postoperative complications following surgery, and also to gain a greater understanding of the role of lipid peroxidation in diabetes and heart failure.
Polyunsaturated fatty acids constitute >50% of all phospholipid acyl chains in biological membranes. Lipid peroxides are formed in cells as a result of PUFA oxidation. When lipid peroxides persist, reactive aldehydes are generated, which constitute a major portion of carbonyl stress in vivo. Using rodent models of diet-induced obesity/insulin resistance, we are examining the mechanisms by which lipid peroxidation in mitochondria and nucleus contribute to cardiac structural and metabolic remodeling. The focus here is on mitochondrial and nuclear isoforms of glutathione peroxidase-4 (GPx4), a lipid peroxide-specific antioxidant enzyme. Thus, we are interested in how these lipid-derived aldehydes cause adducts and disrupt enzyme activity and redox balance, particularly in mitochondria, and the intracellular signaling pathways involved. From a pharmaceutical perspective, we are also interested in development of novel carbonyl-scavenging compounds that form adducts with these aldehydes and serve as interventional tools to specifically target reactive aldehydes (e.g., 4-HNE, Iso-LG’s, MDA, etc).