Disrupting Interleukin 12 Improves Microvascular Endothelial Function in Type 2 Diabetes Through ER Stress CHOP and Oxidative Stress Mechanisms

Abstract

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.

Keywords:

• type 2 diabetes
• interleukin-12
• ER stress
• microvascular endothelial dysfunction
• oxidative stress

Acknowledgments

The abstract of this paper was presented at the American Heart Association’s 2019 Scientific Sessions meeting as a poster presentation with interim findings. The poster’s abstract was published in “Poster Abstracts” in 2019 Journal name Circulation.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

The Study is supported by Funding from the NIH HL150014 (KM) and NIH HL151616 (KM).