Down-regulation of AMPK/PPARδ signalling promotes endoplasmic reticulum stress-induced endothelial dysfunction in adult rat offspring exposed to maternal diabetes

Abstract

Aims Exposure to maternal diabetes is associated with increased prevalence of hypertension in the offspring. The mechanisms underlying the prenatal programming of hypertension remain unclear. Because endoplasmic reticulum (ER) stress plays a key role in vascular endothelial dysfunction in hypertension, we investigated whether aberrant ER stress causes endothelial dysfunction and high blood pressure in the offspring of dams with diabetes. Methods and results Pregnant Sprague-Dawley rats were intraperitoneally injected with streptozotocin (35 mg/kg) or citrate buffer at Day 0 of gestation. Compared with control mother offspring (CMO), the diabetic mother offspring (DMO) had higher blood pressure and impaired endothelium-dependent relaxation in mesenteric arteries, accompanied by decreased AMPK phosphorylation and PPARδ expression, increased ER stress markers, and reactive oxygen species (ROS) levels. The inhibition of ER stress reversed these aberrant changes in DMO. Ex vivo treatment of mesenteric arteries with an AMPK agonist (A769662) or a PPARδ agonist (GW1516) improved the impaired EDR in DMO and reversed the tunicamycin-induced ER stress, ROS production, and EDR impairment in mesenteric arteries from CMO. The effects of A769662 were abolished by co-treatment with GSK0660 (PPARδ antagonist), whereas the effects of GW1516 were unaffected by Compound C (AMPK inhibitor). Conclusion These results suggest an abnormal foetal programming of vascular endothelial function in offspring of rats with maternal diabetes that is associated with increased ER stress, which can be ascribed to down-regulation of AMPK/PPARδ signalling cascade.

Irisin attenuates ventilator‐induced diaphragmatic dysfunction by inhibiting endoplasmic reticulum stress through activation of AMPK

“…AMPK is a serine kinase with a wide range of biological roles. Stressors such as inflammation, hypoxia and oxidative stress can promote AMPK phosphorylation and compensate for its anti‐inflammatory and anti‐ER stress effects 52–54 . Our data suggest that irisin increases the level of phosphorylated AMPK.…”

“…Stressors such as inflammation, hypoxia and oxidative stress can promote AMPK phosphorylation and compensate for its anti-inflammatory and anti-ER stress effects. [52][53][54] Our data suggest that irisin increases the level of phosphorylated AMPK. Whether irisin activates AMPK directly or through some intermediate receptor has not been determined.…”

MiR-206 may regulate mitochondrial ROS contribute to the progression of Myocardial infarction via TREM1

“…Our findings may reveal an important role for miR-206 in inducing ECs senescence and ER stress and provide a fresh perspective on miRNA in the progression of AS and MI. In addition, according to earlier research, AMPK phosphorylation and activation are associated with ER stress [ 64 ] and cell senescence [ 65 ]. We found that the phosphorylation and activation of AMPK were reduced when miR-206 was overexpressed.…”

Research Progress of Maternal Metabolism on Cardiac Development and Function in Offspring

“…Additionally, genes associated with cardiac lipid metabolism, such as PPARα and PGC-1, were downregulated in the fetal and neonatal hearts of diabetic dams, potentially affecting heart energy utilization and cardiomyocyte cell cycle regulation [77,78]. Nutritional disturbances during intrauterine development can also lead to cardiac dysfunction, potentially via dysregulated AMPK/PPARα signaling and impaired vascular endothelial function in offspring of rats with gestational diabetes [79].…”