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TRAF3IP2 (TRAF3 Interacting Protein 2) Mediates Obesity-Associated Vascular Insulin Resistance and Dysfunction in Male Mice
Hypertension ( IF 8.3 ) Pub Date : 2020-10-01 , DOI: 10.1161/hypertensionaha.120.15262
Zachary I Grunewald 1, 2 , Francisco I Ramirez-Perez 2, 3 , Makenzie L Woodford 1, 2 , Mariana Morales-Quinones 2 , Salvador Mejia 2 , Camila Manrique-Acevedo 2, 4, 5 , Ulrich Siebenlist 6 , Luis A Martinez-Lemus 2, 3, 7 , Bysani Chandrasekar 2, 5, 7, 8 , Jaume Padilla 1, 2
Affiliation  

Supplemental Digital Content is available in the text. Insulin resistance in the vasculature is a characteristic feature of obesity and contributes to the pathogenesis of vascular dysfunction and disease. However, the molecular mechanisms underlying obesity-associated vascular insulin resistance and dysfunction remain poorly understood. We hypothesized that TRAF3IP2 (TRAF3 interacting protein 2), a proinflammatory adaptor molecule known to activate pathological stress pathways and implicated in cardiovascular diseases, plays a causal role in obesity-associated vascular insulin resistance and dysfunction. We tested this hypothesis by employing genetic-manipulation in endothelial cells in vitro, in isolated arteries ex vivo, and diet-induced obesity in a mouse model of TRAF3IP2 ablation in vivo. We show that ectopic expression of TRAF3IP2 blunts insulin signaling in endothelial cells and diminishes endothelium-dependent vasorelaxation in isolated aortic rings. Further, 16 weeks of high fat/high sucrose feeding impaired glucose tolerance, aortic insulin-induced vasorelaxation, and hindlimb postocclusive reactive hyperemia, while increasing blood pressure and arterial stiffness in wild-type male mice. Notably, TRAF3IP2 ablation protected mice from such high fat/high sucrose feeding-induced metabolic and vascular defects. Interestingly, wild-type female mice expressed markedly reduced levels of TRAF3IP2 mRNA independent of diet and were protected against high fat/high sucrose diet-induced vascular dysfunction. These data indicate that TRAF3IP2 plays a causal role in vascular insulin resistance and dysfunction. Specifically, the present findings highlight a sexual dimorphic role of TRAF3IP2 in vascular control and identify it as a promising therapeutic target in vasculometabolic derangements associated with obesity, particularly in males.

中文翻译:

TRAF3IP2(TRAF3 相互作用蛋白 2)介导雄性小鼠肥胖相关的血管胰岛素抵抗和功能障碍

补充数字内容在文本中可用。脉管系统中的胰岛素抵抗是肥胖症的特征,并且有助于血管功能障碍和疾病的发病机制。然而,肥胖相关血管胰岛素抵抗和功能障碍的分子机制仍然知之甚少。我们假设 TRAF3IP2(TRAF3 相互作用蛋白 2),一种已知可激活病理应激途径并与心血管疾病有关的促炎适配器分子,在肥胖相关的血管胰岛素抵抗和功能障碍中起因果作用。我们通过在体外内皮细胞、离体离体动脉和体内 TRAF3IP2 消融小鼠模型中饮食诱导的肥胖中采用基因操作来测试这一假设。我们表明 TRAF3IP2 的异位表达减弱了内皮细胞中的胰岛素信号传导,并减少了孤立的主动脉环中依赖于内皮的血管舒张。此外,16 周的高脂肪/高蔗糖喂养会损害葡萄糖耐量、主动脉胰岛素诱导的血管舒张和后肢闭塞后反应性充血,同时增加野生型雄性小鼠的血压和动脉僵硬度。值得注意的是,TRAF3IP2 消融保护小鼠免受这种高脂肪/高蔗糖喂养引起的代谢和血管缺陷。有趣的是,野生型雌性小鼠的 TRAF3IP2 mRNA 水平显着降低,不受饮食的影响,并且可以防止高脂肪/高蔗糖饮食引起的血管功能障碍。这些数据表明 TRAF3IP2 在血管胰岛素抵抗和功能障碍中起因果作用。具体来说,
更新日期:2020-10-01
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