The Role of Shear-Sensitive Protein Heart of Glass Homolog 1 (HEG1) in Endothelial Biology and Atherosclerosis Restricted; Files & ToC

Tamargo, Ian (Spring 2023)

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Atherosclerotic diseases such as myocardial infarction, ischemic stroke, and peripheral arterial disease continue to be leading causes of death worldwide despite the success of cholesterol-lowering drugs and drug-eluting stents, raising the dire need to identify additional therapeutic targets. Interestingly, atherosclerosis preferentially develops in curved and branching arterial regions, where endothelial cells are exposed to disturbed blood flow with characteristic low-magnitude and oscillatory shear stress. In contrast, straight arterial regions exposed to stable flow, associated with high-magnitude, unidirectional shear stress, are relatively well protected from the disease through shear-dependent, atheroprotective endothelial responses, such as induction of atheroprotective protein expression. In the current study, heart of glass homolog 1 (HEG1) is identified as a stable flow-induced endothelial protein. HEG1 is an endothelial-enriched single-pass transmembrane glycoprotein that is essential for vascular development and integrity. 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. To test this hypothesis, mechanistic and functional responses to stable flow in endothelial cells with and without HEG1 expression were compared using an in vitro cone and plate shear system. HEG1 expression was found to be necessary for stable flow-induced Krüppel-like factor 2 and 4 (KLF2/4) expression, two critical transcription factors that control the majority of flow-sensitive endothelial genes. HEG1 expression was also required to mediate the pro-alignment, anti-inflammatory, anti-permeability, anti-migratory and anti-angiogenic effects of stable flow. Using the in vivo partial carotid ligation model of acute atherosclerosis, inducible endothelial cell HEG1 knockout mice (HEG1iECKO) were found to have decreased endothelial KLF2/4 expression, and to have more extensive atherosclerotic plaques as compared to controls. Together, these data indicate that HEG1 protein is required to mediate many atheroprotective effects of stable flow via control of KLF2/4 expression, and that HEG1 is a promising new therapeutic target for atherosclerosis.

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