TRAF3IP2 (TRAF3 Interacting Protein 2) Mediates Obesity-Associated Vascular Insulin Resistance and Dysfunction in Male Mice
| Autor: | Mariana Morales-Quinones, Zachary I. Grunewald, Jaume Padilla, Salvador Mejia, Camila Manrique-Acevedo, Bysani Chandrasekar, Luis A. Martinez-Lemus, Makenzie L Woodford, Ulrich Siebenlist, Francisco I. Ramirez-Perez |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty biology business.industry 030204 cardiovascular system & hematology medicine.disease Proinflammatory cytokine Endothelial stem cell Impaired glucose tolerance Pathogenesis 03 medical and health sciences Insulin receptor 030104 developmental biology 0302 clinical medicine Insulin resistance Endocrinology Internal medicine Internal Medicine biology.protein Medicine Ectopic expression business Reactive hyperemia |
| Zdroj: | Hypertension. 76:1319-1329 |
| ISSN: | 1524-4563 0194-911X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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