Abstract 18133: Inducible, Endothelial Cell-Specific Knockout of Heg1 Exacerbates Atherosclerosis Development in Mice

Abstract

Introduction: Stable blood flow patterns in straight, non-branching regions of the vasculature protect against atherosclerosis by inducing expression of atheroprotective proteins in endothelial cells. Heart of glass homolog 1 (HEG1), a recently-identified, stable flow-induced endothelial protein, is a single-pass transmembrane glycoprotein that has been shown to be essential for vascular development and integrity. Hypothesis: Due to its demonstrated importance in vascular biology, and its induction by stable flow, HEG1 was hypothesized to mediate atheroprotective endothelial responses to stable flow and protect against atherosclerotic plaque formation. Methods: To test the effect of HEG1 expression on atherosclerosis development, inducible endothelial cell-specific HEG1 knockout mice (HEG1 iECKO ) were generated, and exposed to hypercholesterolemia- and flow-induced models of atherosclerosis. Atherosclerotic plaque development, as well as vascular functional and mechanistic responses were compared between HEG1 iECKO and littermate control mice. Results: HEG1 expression was found to be necessary for endothelial Krüppel-like factor 2 and 4 (KLF2/4) expression, two critical transcription factors that control the majority of flow-sensitive endothelial gene transcription. HEG1 iECKO mice were found to have more extensive and advanced atherosclerotic plaques as compared to littermate controls. Conclusions: Together, these data indicate that HEG1 is an atheroprotective protein that mediates beneficial effects of stable flow on vascular endothelial cells, likely via control of KLF2/4 expression, and that HEG1 may be a promising new drug target for the treatment of atherosclerosis.