Multimodal regulation of endothelial-dependent atherosclerosis and inflammation

Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cellular and Molecular Physiology

First Advisor

Suarez, Yajaira

Abstract

Atherosclerosis, driven by altered lipid homeostasis and chronic vascular inflammation, arises through the metabolic and inflammatory perturbation of numerous cell types, including immune cells and endothelial cells (ECs). In fact, inflammation and lipid/glucose metabolism are known to influence each other to orchestrate EC function. Accordingly, expanding our understanding of how EC metabolism and inflammation are regulated could facilitate identification of new modalities to treat atherosclerosis and cardiovascular disease. Here, we postulate that microRNA-33 (miR-33) and Liver X Receptors (LXRs) are central regulators of EC lipid metabolism and inflammation in atherosclerosis development. Importantly, both factors have been linked to lipid metabolism and inflammatory responses of immune cells. Several studies have investigated their impact on atherosclerosis progression using predominantly constitutive knockout mice models or systemic pharmacological agonism and inhibition. However, these studies present with mixed findings, pointing to context- and cell-type-specific functions. Notably, the role of miR-33 and LXRs specifically in ECs in vascular inflammation and atherosclerosis remains unexplored, despite the central involvement of metabolic and inflammatory pathways in EC-driven atherogenesis. In this thesis, mice with inducible EC-specific deletion of miR-33 or LXRs were fed western diet to induce atherosclerosis. Together, these experiments have revealed that while EC-specific knockout of miR-33 promotes lesion initiation in early atherogenesis, it does not impact the development of advanced plaques. Rather, the role of miR-33 in EC is more relevant in shorter-term normolipidemic inflammation, which we confirmed through analyzing acute inflammation in mice with or without miR-33 in EC. This work uncovers a previously unrecognized role for miR-33 in acute inflammation, and highlights how post-transcriptionally linked metabolic perturbations in this cell type can control broader inflammatory functions. On the other hand, we found that EC knockout of LXRs massively accelerates atherosclerosis initiation and progression, leading to the formation of fibrotic and stenotic plaques that obstruct blood flow. This phenotype is associated with a significant decrease in cardiac function, which likely occurs downstream of plaque growth and obstruction of the aortic valve. In this vein, we unexpectedly observed a significant thickening of aortic valve leaflets with evidence of stenosis in mice with loss of LXR in EC, uncovering a novel role for EC LXRs in controlling aortic valve pathology. State-of-the-art multiomics analyses conducted in cultured human aortic EC reveal that LXRs significantly alter the lipid composition and chromatin accessibility of EC, which leads to activation of NFkB signaling and AP-1 activity as well. Through this study, we have identified EC LXRs as extremely potent regulators of EC inflammation and atherosclerosis, which implies that these factors act as essential homeostatic brakes to prevent severe disease. Altogether, these studies highlight how complementary post-transcriptional and transcriptional mechanisms can regulate EC lipid metabolism and function in inflammation, and underscore the necessity to further understand how these pathways are co- and counter-regulated in vascular inflammation and disease.

This document is currently not available here.

Share

COinS