From the Department of Nutrition and Exercise Physiology (Z.I.G., M.L.W., J.P.), University of Missouri, Columbia.
Dalton Cardiovascular Research Center (Z.I.G., F.I.R.-P., M.L.W., M.M.-Q., S.M., C.M.-A., L.A.M.-L., B.C., J.P.), University of Missouri, Columbia.
Hypertension. 2020 Oct;76(4):1319-1329. doi: 10.1161/HYPERTENSIONAHA.120.15262. Epub 2020 Aug 24.
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 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, 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.
血管胰岛素抵抗是肥胖的一个特征，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知之甚少。我们假设 TRAF3IP2（TRAF3 相互作用蛋白 2），一种已知激活病理应激途径的促炎衔接分子，并与心血管疾病有关，在肥胖相关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、离体动脉和体内肥胖小鼠模型中进行基因操作来验证这一假设。我们表明，TRAF3IP2 的异位表达会削弱内皮细胞中的胰岛素信号，并减弱分离的主动脉环中的内皮依赖性血管舒张。此外，16 周高脂肪/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性再充血反应，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，基因敲除可保护小鼠免受高脂肪/高蔗糖喂养引起的代谢和血管缺陷。有趣的是，野生型雌性小鼠无论饮食如何，TRAF3IP2 mRNA 的表达水平明显降低，并能抵抗高脂肪/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，本研究结果突出了 TRAF3IP2 在血管控制中的性别二态作用，并将其确定为与肥胖相关的血管代谢紊乱的有前途的治疗靶点，尤其是在男性中。
