Disrupting Interleukin 12 Improves Microvascular Endothelial Function in Type 2 Diabetes Through ER Stress CHOP and Oxidative Stress Mechanisms.
Disrupting Interleukin 12 Improves Microvascular Endothelial Function in Type 2 Diabetes Through ER Stress CHOP and Oxidative Stress Mechanisms.
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DOI：
10.2147/dmso.s369488
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发表时间：
2022
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影响因子：
--
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中科院分区：
文献类型：
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血管内皮功能障碍在2型糖尿病中已得到充分证实。白细胞介素-12（IL-12）和内质网（ER）应激在2型糖尿病患者和2型糖尿病动物模型中上调。然而，IL-12和ER应激CHOP在内皮功能障碍中的作用和潜在机制尚不完全清楚。我们在db−/db−和p40 IL-12−/−小鼠（db−/db−p40-IL−12-/-）和内质（ER）应激-CHOP −/−小鼠（db−/db−CHOP-/-）之间产生了双敲除小鼠。我们进行了葡萄糖耐量试验（GTT），以确定IL-12和ER应激CHOP对葡萄糖代谢的影响。我们评估了内皮功能，并测定了eNOS、Akt、AMPK的磷酸化水平，以及ER应激（CHOP、BIP）和氧化应激（Nox 2和Nox 4以及NADPH氧化酶活性）的表达。结果表明，在db-/db−p40-IL−12-/-和db−/db−CHOP-/-中，GTT得到改善，表明IL-12和CHOP是参与2型糖尿病发展的机制的一部分。db−/db−小鼠的微血管内皮功能障碍与磷酸化eNOS、Akt、AMPK的降低以及CHOP、BIP、Nox 2和Nox 4表达的增加有关。有趣的是，在db−/db−小鼠中破坏IL-12和ER应激CHOP显著改善了内皮功能，增加了生存标志物表达，降低了ER和氧化应激。使用遗传学方法，这些研究结果提供了证据表明IL-12和ER应激CHOP在2型糖尿病微血管内皮功能障碍中起重要作用。
Vascular endothelial dysfunction is well established in type 2 diabetes. Interleukin-12 (IL-12) and endoplasmic reticulum (ER) stress are up-regulated in type 2 diabetic patients and animal models of type 2 diabetes. However, the role and underlying mechanisms of IL-12 and the ER stress CHOP in endothelial dysfunction are not fully understood. We generated double knockout mice between db−/db− and p40IL-12−/− mice (db−/db−p40-IL−12-/-) and endoplasmic (ER) stress-CHOP−/− mice (db−/db−CHOP-/-). We performed a glucose tolerance test (GTT) to determine the effect of IL-12 and ER stress CHOP on glucose metabolism. We assessed the endothelial function and determined the phosphorylation level of eNOS, Akt, AMPK, and the expression of ER stress (CHOP, BIP), and oxidative stress (Nox2 and Nox4 and NADPH oxidase activity). The results showed that GTT was improved in db-/db−p40-IL−12-/- and db−/db−CHOP-/- suggesting IL-12 and CHOP as parts of a mechanism involved in the development of type 2 diabetes. The microvascular endothelial dysfunction in db−/db− mouse is associated with decreased phosphorylated eNOS, Akt, AMPK, and increased CHOP, BIP, Nox2, and Nox4 expressions. Interestingly, disrupting IL-12 and ER stress CHOP in db−/db− mice significantly improved endothelial function, increased survival markers expression and decreased ER and oxidative stress. Using a genetic approach, these findings provide evidence that IL-12 and ER stress CHOP play a significant role in microvascular endothelial dysfunction in type 2 diabetes.
影响因子：
4.6
作者：
McKimpson WM;Zheng M;Chua SC;Pessin JE;Kitsis RN
通讯作者：
Kitsis RN