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Disrupting Interleukin 12 Improves Microvascular Endothelial Function in Type 2 Diabetes Through ER Stress CHOP and
Eman Radwan1,2, Souad Belmadani1, Khalid Matrougui1
1Department of Physiological Sciences, EVMS, Norfolk, VA, 23501, USA.
Purpose:
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.
Methods:
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).
Results:
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.
Conclusion:
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.
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