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The Nexus Between Endothelial Cell Homeostasis and Cholesterol Regulation

Abstract

Maintaining vascular endothelial cell (EC) homeostasis is integral to preventing cardiovascular disease. Here, we demonstrate that EC function is tightly regulated with cholesterol homeostasis. The reciprocal cholesterol efflux and cholesterol biosynthesis pathways also contribute to EC function or dysfunction, respectively. This study focuses on a two-pronged approach: 1) How a key regulator of EC function, namely Krüppel-like factor 4 (KLF4), relates to cholesterol efflux and oxidation to promote an anti-inflammatory and anti-oxidative effect in ECs to prevent cardiovascular disease; and 2) How key mediators of cholesterol biosynthesis, i.e., sterol regulatory element-binding protein 2 (SREBP2), relate to the regulation of EC dysfunction contributing to cardiovascular disease. To investigate both pathways, I began with a systems biology approach by using RNA-sequencing of ECs in which KLF4 or SREBP2 is overexpressed. From this global view, novel pathways regulated by KLF4 or SREBP2 that exert opposing functional outcome in ECs were identified. Furthermore, KLF4 was demonstrated to promote endothelial homeostasis in part through the activation of cholesterol oxidation and efflux via the induction of cholesterol-25-hydroxylase (Ch25h) and liver X receptor (LXR). Additionally, KLF4-regulated suppression of the pro-inflammatory SREBP2 and NLRP3 inflammasome pathway contributed to an athero-protective phenotype in mice, further defining that KLF4 regulates a counterbalance between LXR and SREBP2. In contrast, SREBP2 was determined to be both necessary and sufficient to induce EC dysfunction through the upregulation of endothelial-to-mesenchymal transition (EndoMT). This is further implicated in the pro-fibrotic cardiovascular disease, idiopathic pulmonary fibrosis. This two-sided and reciprocal approach provided evidence that cholesterol homeostasis must be tightly regulated by KLF4 in order to maintain EC function. Moreover, when cholesterol regulation is shifted towards SREBP2, ECs become dysfunctional leading to exacerbated cardiovascular disease. The opposing functions of these two key transcription factors provide insight into the complex regulatory network between EC function and cholesterol balance.

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