Omentin-1 protects against endothelial dysfunction through the AMPK/KLF2/eNOS pathway in adult rat offspring exposed to maternal diabetes.

Abstract

Objective: Exposure to gestational diabetes mellitus appears to produce several effects on offspring, including increased rates of early-onset cardiovascular disease from childhood to early adulthood. In this study, we investigated the protection of human omentin-1 against endothelial dysfunction resulting from exposure to maternal diabetes in adult rat offspring.

Methods: Twelve adult control mother offspring (CMO) were injected with rh-omentin or saline, and 12 adult diabetic mother offspring (DMO) were injected with rh-omentin or saline. The mesenteric artery rings of rh-omentin-injected DMO were incubated with Compound C (an AMPK inhibitor). The vascular reactivity of rat mesenteric artery rings was evaluated by treating with PE (10^-9-10^-5M) and Ach (10^-9-10^-5M). The mesenteric arterial endothelial cells (AECs) isolated from different groups were incubated with A769662 (an AMPK agonist) and/or transfected with siRNA against KLF2 (si-KLF2) to confirm the AMPK/KLF2 pathway involved in the protection of omentin-1 against endothelial dysfunction.

Results: Injection of rh-omentin alleviated PE-induced vasoconstriction and improved Ach-induced vasorelaxation in the mesenteric artery rings, inhibited phosphorylations of endoplasmic reticulum (ER) stress markers, prevented loss of phosphorylations of AMPK and endothelial nitric-oxide synthase (eNOS), increased nitric oxide production, reduced the level of reactive oxygen species, and promoted KLF2 expression in DMO. The AMPK inhibitor and KLF2 knockdown both eliminated these effects of omentin-1 on adult rat offspring exposed to maternal diabetes. KLF2 knockdown also weakened the effects of the AMPK agonist on adult rat offspring exposed to maternal diabetes.

Conclusion: These findings point out that mentin-1 could protect adult rat offspring against endothelial dysfunction, including endothelium impairment, ER stress, and oxidative stress resulting from exposure to maternal diabetes through the AMPK/KLF2/eNOS pathway.