HDL Regulates TGFβ-Receptor Lipid Raft Partitioning, Restoring Contractile Features of Cholesterol-Loaded Vascular Smooth Muscle Cells

IF 8.4 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

JACC: Basic to Translational Science Pub Date : 2026-03-01 Epub Date: 2026-02-12 DOI:10.1016/j.jacbts.2025.101461

Prashanth Thevkar Nagesh PhD , Shruti Rawal PhD , Hitoo Nishi PhD , Tarik Zahr BS , Joseph M. Miano PhD , Mary Sorci-Thomas PhD , Hao Xu PhD , Naveed Akbar PhD , Robin P. Choudhury DM , Mark W. Feinberg MD , Ashish Misra PhD , Edward A. Fisher MD, PhD

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引用次数: 0

Abstract

Many cells identified as macrophage-like in human and mouse atherosclerotic plaques are thought to be of vascular smooth muscle cell (VSMC) origin. We identified cholesterol-mediated down-regulation of TGFβ signaling in vitro in human (h)VSMCs by localization of TGFβ receptors in membrane lipid rafts, which was reversed by high-density lipoprotein (HDL)-mediated cholesterol efflux. This restored VSMC contractile marker (Acta2) and suppressed macrophage marker (CD68) expression by promoting TGFβ enhancement of Mir145 expression. In vivo, administration of ApoA1 (which forms HDL) to atherosclerotic mice also promoted VSMC Acta2 expression and reduced CD68 expression. Because macrophage-like VSMCs are thought to have adverse properties, our studies not only show mechanistically how cholesterol causes their transition, but also suggest that efflux-competent HDL particles may have a therapeutic role by restoring a more favorable phenotypic state of VSMCs in atherosclerotic plaques.

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高密度脂蛋白调节tgf β受体脂筏分配，恢复胆固醇负荷血管平滑肌细胞的收缩特征

人类和小鼠动脉粥样硬化斑块中许多巨噬细胞样细胞被认为起源于血管平滑肌细胞（VSMC）。我们在体外通过膜脂筏中TGFβ受体的定位，在人(h)VSMCs中发现了胆固醇介导的TGFβ信号下调，这一过程被高密度脂蛋白（HDL）介导的胆固醇外排逆转。通过促进TGFβ增强Mir145的表达，恢复VSMC收缩标志物（Acta2）并抑制巨噬细胞标志物（CD68）的表达。在体内，给动脉粥样硬化小鼠ApoA1（形成HDL）也促进VSMC Acta2表达和降低CD68表达。由于巨噬细胞样VSMCs被认为具有不良特性，我们的研究不仅从机制上揭示了胆固醇是如何导致其转变的，而且还表明，外溢能力强的HDL颗粒可能通过恢复动脉粥样硬化斑块中VSMCs更有利的表型状态而具有治疗作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

JACC: Basic to Translational Science CARDIAC & CARDIOVASCULAR SYSTEMS-

CiteScore

14.20

自引率

1.00%

发文量

161

审稿时长

16 weeks

期刊介绍： JACC: Basic to Translational Science is an open access journal that is part of the renowned Journal of the American College of Cardiology (JACC). It focuses on advancing the field of Translational Cardiovascular Medicine and aims to accelerate the translation of new scientific discoveries into therapies that improve outcomes for patients with or at risk for Cardiovascular Disease. The journal covers thematic areas such as pre-clinical research, clinical trials, personalized medicine, novel drugs, devices, and biologics, proteomics, genomics, and metabolomics, as well as early phase clinical trial methodology.