Suppressing or blocking Fis1 reverses diabetic endothelial dysfunction in human resistance arteries

Abstract

AbstractMitochondrial dysfunction drives the development of vascular endothelial dysfunction in type 2 diabetes (T2DM) with increased fragmentation of mitochondrial networks from increased Fis1 expression; whether suppressing or blocking Fis1 expression or activity can reverse endothelial dysfunction remains unknown. To address this question, resistance arterioles from healthy humans and those with T2DM were transfected with Fis1 siRNA and exposed to normal glucose, low glucose or high glucose conditions. Fis1 knockdown improved endothelium dependent vasodilation in T2DM arterioles, and blocked high- and low-glucose impairment in healthy vessels. Fis1 knockdown preserved NO bioavailability and improved endothelial layer integrity of cells exposed to high or low glucose. Fis1 knockdown had no significant effect on the expression of other mitochondrial dynamics or autophagy proteins, and had no effect on endothelial cell metabolism suggesting its suitability for pharmacological inhibition. For this, we designed pep213 to inhibit Fis1 activity (Kd ~3-7 μM) and demonstrate its specificity by NMR. Application of a cell permeant pep213 improved endothelium-dependent vasodilation in T2DM and non-T2DM vessels exposed to high glucose in an NO-dependent manner suggesting that targeting Fis1 may reduce vascular complications in T2DM.One Sentence SummaryMicro- and macro-vascular complications in type 2 diabetes mellitus (T2DM) continue to be major health burdens in the United States and we identify a new therapeutic route to treatment by showing that either a novel peptide inhibitor, or genetic silencing, of mitochondrial fission protein 1 reverses poor vasodilation of human resistance arteries from diabetic patients.