Abnormal ER and mitochondrial communication underlies ER stress in cerebrovascular insulin resistance

Abstract

We previously demonstrated impaired mitochondria (mito)‐mediated vasodilation, abnormal mitochondrial Ca2+ uptake and vascular insulin resistance (IR) in cerebral arteries of Zucker obese rats (ZO). Mitofusin 2 (MFN2) tethers mitochondria to endoplasmic reticulum (ER) and creates Ca2+microdomains of interorganelle communication. Our objective is to elucidate the impact of IR on ER‐mito interaction. Expression levels of key mitochondrial proteins (MFN2 and VDAC) and ER stress markers (immunoglobin heavy chain binding protein (BiP), C/EB‐Phomologous protein (CHOP), and X‐box binding protein 1 (XBP1)) and phosphorylated neuronal nitric oxide synthase (p‐nNOS) was determined. Isolated cerebral arteries from ZO and their lean (ZL) controls were treated with vehicle or insulin (1mU/ml) under normal and oxygen‐glucose deprived (OGD) conditions for 4 hours. ZO arteries displayed decreased MFN2 and VDAC and increased CHOP, BiP, XBP1 and nNOS at baseline. Insulin+OGD treatment increased MFN2 and p‐nNOS but reduced BiP in ZL whereas it promoted decreased MFN2 and p‐nNOS but increased BiP in ZO. Thus, ZO arteries with IR display impaired mito‐ER communication at baseline which is further enhanced by insulin under OGD.