The role of the epicardium and IRE1 in mediating environmental exposure on cardiac function

About This Grant

Advances in cell culture techniques and stem cell technology have enabled generation of 3- dimensional organoids capable of recapitulating the structure and physiology of human organs better than 2D cultures. These organoids can aid in identifying early biomarkers of diseases, and understanding the impact of environmental factors on the initiation and progression of diseases. We recently used our human heart organoids (hHOs) derived from human induced pluripotent stem cells (iPSCs) to explore changes in lipid profile mediated by endoplasmic reticulum (ER) stress sensor proteins. Exogenous chemicals (e.g., per-and polyfluoroalkyl substances (PFAS), drugs, etc.) and endogenous metabolites (e.g., cholesterol and saturated fatty acids (SFAs)) negatively affect cardiac function. PFAS are found in many household cleaning products and commercial packaging materials. Once released to the environment, these “forever chemicals” degrade slowly, resulting in detectable levels in drinking water, food, and animals, including humans. PFAS are ubiquitous environmental contaminants that also accumulate in the food chain, which is one of the main routes of human exposure. Evidence have linked PFAS to altered lipid profile and cardiovascular disease (CVD). We and others have found that PFAS induces ER stress, notably inositol-requiring enzyme 1α (IRE1α) signaling. ER stress and activation of IRE1α is involved in various conditions that advance heart diseases. Thus far, studies on the changes in lipid composition induced by PFAS has been limited to cholesterol, lipoproteins and TG. We found that (i) IRE1α mediates changes in the lipid profile (notably, long-chain fatty acids) in our hHOs, and (ii) PFAS activates IRE1α signaling and is linked to dyslipidemia and CVD risk. Therefore, we hypothesize that PFAS activation of IRE1α signaling alters the lipid profiles and negatively affects cardiac function. We further propose that our organoids, which contain epicardial cells (that provide trophic factors and can mediate lipid metabolism) in addition to cardiomyocytes, enable investigation of the influence of epicardial cells on the cardiac lipid profile and function. In the first aim, we will investigate the changes in lipid content (i.e., very long chain long chain fatty acids: odd and even) and cardiac function induced by PFAS exposure and mediated by IRE1α. In the second aim, we will investigate the PFAS-induced changes in lipid profile and cardiac function mediated by the epicardium.