Abstract 24035: Human iPSC-Derived Endothelial Cells Predict Predilection to Atherogenesis by Endothelial Proinflammatory Activation

Abstract

Introduction: Coronary artery disease (CAD), the direct outcome of atherosclerosis, is the leading cause of death in the United States. Previous studies demonstrated that impaired function of aldehyde dehydrogenase 2 (ALDH2), a key enzyme for alcohol metabolism, is linked to increased susceptibility to CAD. A single-nucleotide polymorphism that generates E487K mutation (ALDH2*2) reduces enzymatic activity of ALDH2 to less than 40% of the wild type (WT) and is present in ~560 million people. However, it remains unclear how ALDH2 regulates atherosclerotic progression. Hypothesis: Recent studies suggest a critical role of ALDH2 in plaque development and endothelial activation. Therefore, we hypothesize that endothelial cells of ALDH2*2 carriers possess greater susceptibility to proinflammatory activation, whereby endothelial cells recruit immune cells, leading to increased risk of atherogenesis. Methods: To study the patient-specific effects of ALDH2*2 mutation on endothelial proinflammatory activation, we generated and characterized iPSC-derived endothelial cells (iPSC-ECs) from 5 WT subjects and 5 ALDH2*2 carriers. We exposed the iPSC-ECs to pro-inflammatory conditions and assessed the level of endothelial proinflammatory activation by gene expression analysis and monocyte adhesion assay. Results: Our preliminary data show ALDH2*2-iPSC-ECs exhibit impaired ALDH2 function resulting in metabolic dysregulation compared to WT. Presence of ALDH2*2 mutation resulted in enhanced inflammatory response in the iPSC-ECs when treated with proinflammatory cytokines such as TNFα and IL-1β, as evidenced by up-regulation of cell adhesion molecules and augmented adherence to monocytes. The ALDH2*2-iPSC-ECs also exhibited an increased basal expression of vascular endothelial growth factor receptor 1 (FLT1) gene, which was further augmented upon inflammatory stimulation. FLT1 is a receptor for vascular endothelial growth factor ligands, playing a critical role in endothelial homeostasis and biology. Conclusion: Taken together, we elucidate the effects of impaired ALDH2 function on increased susceptibility to atherogenesis by endothelial proinflammatory activation using patient-derived iPSC-ECs.