Hypercholesterolemia- induced LXR signaling in smooth muscle cells contributes to vascular lesion remodeling and visceral function

• 成果类型: Article
• 署名作者: Zhang, Hanming; de Urturi, Diego Saenz; Fernandez-Tussy, Pablo; Huang, Yan; Jovin, Daniel G.; Zhang, Xinbo; Huang, Shushu; Lek, Monkol; Catarino, Jonatas da Silva; Sternak, Magdalena; Citrin, Kathryn M.; Swirski, Fillip K.; Gustafsson, Jan - ake; Greif, Daniel M.; Esplugues, Enric; Biwer, Lauren A.; Suarez, Yajaira; Fernandez-Hernando, Carlos
• 署名单位: Yale University; Yale University; Yale University; Yale University; Yale University; Jagiellonian University; Yale University; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; University of Houston System; University of Houston; Yale University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10592
• DOI: 10.1073/pnas.2417512122
• 发表日期: 2025-03-04
• 关键词: liver-x-receptor; endoplasmic-reticulum stress; cholesterol efflux; lipid-metabolism; acid synthesis; retinoic acid; er stress; atherosclerosis; ligand; alpha

摘要

Vascular smooth muscle cells (VSMC) are the most abundant cell type in the artery's media layer and regulate vascular tone and lesion remodeling during atherogenesis. Like monocyte-derived macrophages, VSMCs accumulate excess lipids and contribute to the total intimal foam cell population in human coronary plaques and mouse aortic atheroma. While there are extensive studies characterizing the contribution of lipid metabolism in macrophage immunometabolic responses in atherosclerotic plaques, the role of VSMC lipid metabolism in regulating vascular function and lesion remodeling in vivo remains poorly understood. Here, we report that the liver X receptor (LXR) signaling pathway in VSMC is continuously activated during atherogenesis. Notably, we found that LXR deficiency in SMCs under hypercholesterolemic conditions influenced lesion remodeling by altering the fate of dedifferentiated SMCs and promoting the accumulation of VSMC-derived transitional cells. This phenotypic switching was accompanied by reduced indices of plaque stability, characterized by a larger necrotic core area and reduced fibrous cap thickness. Moreover, SMC-specific LXR deficiency impaired vascular function and caused visceral myopathy characterized by maladaptive bladder remodeling and gut lipid malabsorption. Mechanistically, we found that the expression of several genes involved in cholesterol efflux and FA synthesis including Abca1, Srebf1, Scd1, Scd2, Acsl3, and Mid1ip1 was downregulated in mice lacking LXR alpha beta in SMCs, likely contributing to the phenotypic switching of VSMC in the atherosclerotic lesions.