Modeling the Effect of Apolipoprotein LI Risk Variants on CVD Risk in African American E-cigarette Users Using Human Induced Pluripotent Stem-Cell-Derived Endothelial Cells

/ABSTRACT African American individuals face a disproportionately higher risk of tobacco-related cardiovascular diseases (CVD) than other races, a disparity not fully explained by traditional and socioeconomic risk factors. Despite lacking approval from the U.S. Food and Drug Administration (FDA) for their safety, e-cigarettes (e-cigs) have become increasingly popular, particularly among youth, and are now among the most commonly used tobacco products alongside traditional cigarettes. Approximately half of African American individuals carry at least one of two genetic variants (G1 and G2) of the apolipoprotein L1 (APOL1) gene, which are exceedingly rare in other populations. APOL1 is widely expressed, particularly in the vasculature. We have shown that carriers of APOL1 G1 and G2 variants have increased susceptibility to tobacco-related CVD, including stroke and coronary heart disease. Dysfunction of vascular endothelial cells (ECs) is a critical precursor to CVD. EC dysfunction also plays a key role in APOL1-associated pathology, including exacerbated renal issues and increased susceptibility to sepsis and severe COVID-19. Recent research indicates that, similar to cigarettes, both e-cigs and menthol—a flavor popular in the African American community—independently impair endothelial function. While studies, including those using induced pluripotent stem cell (iPSC)-derived ECs, demonstrate these effects, the specific impact of APOL1 risk variants on vascular health in African American tobacco product users remains unknown. The goal of the proposed research is to determine the effects of e-cigs, with and without menthol, on endothelial health, compare them to the effects of cigarettes, and identify potential molecular markers and pathways associated with CVD in African American users, with a focus on the APOL1 genotype. As such, this application aims to expand my background and expertise in modeling the CVD risk from tobacco products and to provide specific training in tobacco product-related in vitro assays, iPSC methodology, gene editing, and computational techniques. Building on my prior work in human studies, this research extends to the cellular level to address significant gaps in knowledge regarding the adverse effects of the most popular tobacco products, with and without menthol, among the African American population—a demographic long targeted by the tobacco industry marketing. To achieve this goal, I will use a robust in vitro platform of human iPSC-ECs to address the following aims: Aim K1) to determine the effect of e-cigs and cigarettes on markers of EC dysfunction in G1/G1 iPSC-ECs, Aim R1) to determine the effect of e-cigs and cigarettes on endothelial function in G2/G2 iPSC-ECs, and Aim R2) to determine the effect of e-cigs and cigarettes on inflammatory markers and lipid mediators of inflammation in G1/G1 and G2/G2 iPSC-ECs. This project will deepen our understanding of the adverse effects of widely used tobacco products on vascular health in the CVD-burdened African American population. It also aims to identify molecular markers of cardiovascular injury in this high-risk group, providing insights into the mechanisms of tobacco-related cardiovascular damage and supporting the development of targeted interventions. Project Number: 1K99HL183741-01 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Jelena Mustra Rakic | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $127,168 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 IVBH-A (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K99HL18374101