Short-term interleukin-37 treatment improves vascular endothelial function, endurance exercise capacity, and whole-body glucose metabolism in old mice.,Aging Cell

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Short-term interleukin-37 treatment improves vascular endothelial function, endurance exercise capacity, and whole-body glucose metabolism in old mice.
Aging Cell ( IF 8.0 ) Pub Date : 2019-11-21 , DOI: 10.1111/acel.13074
Dov B Ballak _{1,

2} , Vienna E Brunt ₁ , Zachary J Sapinsley ₁ , Brian P Ziemba ₁ , James J Richey ₁ , Melanie C Zigler ₁ , Lawrence C Johnson ₁ , Rachel A Gioscia-Ryan ₁ , Rachel Culp-Hill ₂ , Elan Z Eisenmesser ₂ , Angelo D'Alessandro ₂ , Charles A Dinarello _{2,

3} , Douglas R Seals ₁

Affiliation

Aging is associated with vascular endothelial dysfunction, reduced exercise tolerance, and impaired whole‐body glucose metabolism. Interleukin‐37 (IL‐37), an anti‐inflammatory cytokine of the interleukin‐1 family, exerts salutary physiological effects in young mice independent of its inflammation‐suppressing properties. Here, we assess the efficacy of IL‐37 treatment for improving physiological function in older age. Old mice (26–28 months) received daily intraperitoneal injections of recombinant human IL‐37 (recIL‐37; 1 µg/200 ml PBS) or vehicle (200 ml PBS) for 10–14 days. Vascular endothelial function (ex vivo carotid artery dilation to increasing doses of acetylcholine, ACh) was enhanced in recIL‐37 vs. vehicle‐treated mice via increased nitric oxide (NO) bioavailability (all p < .05); this effect was accompanied by enhanced ACh‐stimulated NO production and reduced levels of reactive oxygen species in endothelial cells cultured with plasma from IL‐37‐treated animals (p < .05 vs. vehicle plasma). RecIL‐37 treatment increased endurance exercise capacity by 2.4‐fold, which was accompanied by a 2.9‐fold increase in the phosphorylated AMP‐activated kinase (AMPK) to AMPK ratio (i.e., AMPK activation) in quadriceps muscle. RecIL‐37 treatment also improved whole‐body insulin sensitivity and glucose tolerance (p < .05 vs. vehicle). Improvements in physiological function occurred without significant changes in plasma, aortic, and skeletal muscle pro‐inflammatory proteins (under resting conditions), whereas pro‐/anti‐inflammatory IL‐6 was greater in recIL‐37‐treated animals. Plasma metabolomics analysis revealed that recIL‐37 treatment altered metabolites related to pathways involved in NO synthesis (e.g., increased L‐arginine and citrulline/arginine ratio) and fatty acid metabolism (e.g., increased pantothenol and free fatty acids). Our findings provide experimental support for IL‐37 therapy as a novel strategy to improve diverse physiological functions in old age.

中文翻译：

短期白介素 37 治疗可改善老年小鼠的血管内皮功能、耐力运动能力和全身葡萄糖代谢。

衰老与血管内皮功能障碍、运动耐量降低和全身葡萄糖代谢受损有关。白细胞介素-37 (IL-37) 是白细胞介素-1 家族的一种抗炎细胞因子，在年轻小鼠中发挥有益的生理作用，与其抑制炎症的特性无关。在这里，我们评估 IL-37 治疗改善老年人生理功能的功效。年老小鼠（26-28 个月）每天腹腔注射重组人 IL-37（recIL-37；1 µg/200 ml PBS）或载体（200 ml PBS），持续 10-14 天。与媒介物治疗小鼠相比，recIL-37 小鼠的血管内皮功能（离体颈动脉扩张以增加乙酰胆碱 (ACh) 剂量）通过增加一氧化氮 (NO) 生物利用度而得到增强（所有p < .05）；这种效应伴随着用 IL-37 处理的动物血浆培养的内皮细胞中 ACh 刺激的 NO 产生增强和活性氧水平降低（与载体血浆相比， p < 0.05）。 RecIL-37 治疗使耐力运动能力提高了 2.4 倍，同时股四头肌中磷酸化 AMP 激活激酶 (AMPK) 与 AMPK 的比率（即 AMPK 激活）增加了 2.9 倍。 RecIL-37 治疗还改善了全身胰岛素敏感性和葡萄糖耐量（与载体相比， p < 0.05）。生理功能的改善发生在血浆、主动脉和骨骼肌促炎蛋白（静息条件下）没有显着变化的情况下，而促/抗炎IL-6在recIL-37治疗的动物中更高。血浆代谢组学分析表明，recIL-37 治疗改变了与 NO 合成相关途径相关的代谢物（例如，增加L-精氨酸和瓜氨酸/精氨酸比率）和脂肪酸代谢（例如，增加泛醇和游离脂肪酸）。我们的研究结果为 IL-37 疗法作为改善老年多种生理功能的新策略提供了实验支持。

更新日期：2019-11-21

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