Creation of a patient-specific endothelial model to investigate the role of DHX34 in early-onset coronary artery disease

Abstract

Coronary artery disease (CAD) is characterized by the development of atherosclerotic plaques in the coronary arteries and is one of the leading causes of global mortality. Despite the fact that CAD presents clinically as changes to myocardial function, it is ultimately a disease of the vessel wall. The endothelial cells that line the inner portion of arteries act as a primary defence system against CAD development and as such, were the focus of our work on early-onset CAD (EOCAD). Through a collaboration with Dr. Paré, exome sequencing was performed on EOCAD patients that resulted in the identification of novel, rare variants in DHX34, a component of the nonsense-mediated mRNA decay (NMD) pathway. Induced pluripotent stem cells (iPSCs) were generated from a small-number of peripheral blood monocytes from these patients using the Sendai virus. A protocol was generated that improved endothelial differentiation efficiency and was subsequently utilized to investigate the role of DHX34 in endothelial cell function. The patient-derived endothelial cells had decreased migratory capacity, increased leukocyte adhesion, and altered nitric oxide signaling, all of which are necessary in maintaining the anti-atherogenic environment of coronary arteries. Although further work is required to elucidate the specific mechanism through which the variants confer their impact, this work suggests that DHX34 plays a role in preventing CAD development.