Habibi Javad, DeMarco Vincent G, Chen Dongqing, Whaley-Connell Adam, Hill Michael A, Jia Guanghong
Department of Medicine-Endocrinology and Metabolism, University of Missouri School of Medicine, Columbia, MO 65212, USA; Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO 65201, USA.
Department of Medicine-Endocrinology and Metabolism, University of Missouri School of Medicine, Columbia, MO 65212, USA; Department of Medicine-Nephrology and Hypertension, University of Missouri School of Medicine, Columbia, MO 65212, USA; Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO 65201, USA.
J Mol Cell Cardiol. 2025 Jun 16;205:52-61. doi: 10.1016/j.yjmcc.2025.06.009.
A Western diet (WD) contributes to the rising prevalence of obesity and insulin resistance, both of which are key risk factors for arterial stiffening and related cardiovascular diseases. We recently found that elevated CD36 is associated with increased ectopic lipid accumulation, systemic and tissue insulin resistance, and arterial stiffening. Here, we further examined whether endothelial cell (EC) specific CD36 (ECCD36) participates in WD-induced aortic insulin resistance, lipid accumulation, inflammation, fibrosis, remodeling, and associated aortic stiffening. Female ECCD36 knockout (ECCD36) and wild-type (ECCD36) mice, at six weeks of age, were fed either a Western diet (WD) or a standard chow diet (CD) for 16 weeks. Aortic stiffness and activity were investigated by ultrasound (pulse wave velocity) and wire myography, respectively. Gene expression was monitored by western blot and quantitative PCR. Lipid content and aortic remodeling were explored by Oil red O staining and immunostaining, respectively. 16 weeks of WD increased aortic stiffening that was associated with vascular insulin resistance and reduced insulin metabolic signaling via phosphoinositide 3-kinases/protein kinase B. The pathophysiological changes in vascular insulin resistance and stiffening were associated with activation of mammalian target of rapamycin/S6 kinase signaling, increased lipid disorders, decreased tight junction-associated protein occludin, and increased proinflammatory response, and aortic remodeling. These abnormalities were blunted in ECCD36 mice fed a WD. These findings suggest that under an obesogenic Western diet (WD), heightened ECCD36 signaling contributes to aortic insulin resistance, increased lipid accumulation, increased endothelial permeability and proinflammatory responses, fibrosis, vascular remodeling, and consequent aortic stiffening.
西方饮食（WD）导致肥胖和胰岛素抵抗的患病率不断上升，而这两者都是动脉僵硬及相关心血管疾病的关键风险因素。我们最近发现，CD36升高与异位脂质积聚增加、全身和组织胰岛素抵抗以及动脉僵硬有关。在此，我们进一步研究了内皮细胞（EC）特异性CD36（ECCD36）是否参与WD诱导的主动脉胰岛素抵抗、脂质积聚、炎症、纤维化、重塑以及相关的主动脉僵硬。六周龄的雌性ECCD36基因敲除（ECCD36-/-）和野生型（ECCD36+/+）小鼠分别喂食西方饮食（WD）或标准饲料（CD）16周。分别通过超声（脉搏波速度）和线肌描记法研究主动脉僵硬度和活性。通过蛋白质印迹和定量PCR监测基因表达。分别通过油红O染色和免疫染色探索脂质含量和主动脉重塑。16周的WD增加了主动脉僵硬，这与血管胰岛素抵抗以及通过磷酸肌醇3激酶/蛋白激酶B降低的胰岛素代谢信号有关。血管胰岛素抵抗和僵硬的病理生理变化与雷帕霉素靶蛋白/S6激酶信号的激活、脂质紊乱增加、紧密连接相关蛋白闭合蛋白减少、促炎反应增加以及主动脉重塑有关。在喂食WD的ECCD36-/-小鼠中，这些异常情况有所减轻。这些发现表明，在致肥胖的西方饮食（WD）条件下，增强的ECCD36信号传导会导致主动脉胰岛素抵抗、脂质积聚增加、内皮通透性增加和促炎反应、纤维化、血管重塑以及随之而来的主动脉僵硬。
