Transcriptomic Analysis of Nicotine on the Cardiovascular System Using a Diverse Population of Human Induced Pluripotent Stem Cell-derived Endothelial Cells

Nicotine, the primary addictive component of tobacco, is linked to major adverse cardiovascular events (MACE) and increased mortality. The impact of nicotine across diverse populations is challenging to investigate in clinical studies due to individual variations in environmental exposures, the presence of other compounds in cigarettes and e-cigarettes, and differences in nicotine dosage and frequency. While animal models offer control over these variables, translating findings to human physiology remains complex. Induced pluripotent stem cells (iPSCs) present a promising alternative, leveraging each patient's unique genetic profile. In this study, we utilized iPSCs to explore the effects of nicotine on the cardiovascular system in a genetically diverse population. We derived endothelial cells (iPSC-ECs) from iPSCs of 20 healthy donors from diverse ancestries, including African, Caucasian, East Asian, and Hispanic, and exposed them to 1 µM nicotine for 48 hours. RNA sequencing analysis revealed significant interindividual variation in gene expression, while the nicotine-induced transcriptomic signature was consistent across individuals. A total of 399 differentially expressed genes (DEGs) were identified, with 303 downregulated and 96 upregulated genes. Pathway analysis indicated that upregulated genes were associated with cardiovascular diseases and nicotine addiction, whereas downregulated genes were linked to type 2 diabetes and respiratory disorders. Further analysis highlighted nicotine's effect on pathways related to atherosclerosis and type 2 diabetes. Notably, genes such as HMOX1 and HSPA6 were significantly downregulated upon nicotine exposure, findings validated by quantitative real-time PCR. This study underscores the utility of iPSC-ECs in modeling nicotine's direct impact on the endothelium, providing insights into its role in disease pathogenesis and offering potential avenues for the development of diagnostic markers and therapeutic interventions.