Abstract 5515: Mitochondrial Membrane Hyperpolarization and Reduced Mitochondrial Mass Characterize the Arteriolar Endothelium and Mononuclear Cells of Humans With Type 2 Diabetes Mellitus- in vivo and in vitro Assessment of Endothelial Function
Background: Endothelial dysfunction and inflammation are central to the vascular pathology of Type 2 diabetes (DM). In vitro data suggest excessive mitochondrial reactive oxygen species production contributes to endothelial dysfunction in part due to pathological hyperpolarization of mitochondrial membrane potential (ΔΨm). ΔΨm hyperpolarization in leukocytes is also associated with activation of the inflammatory response. Mitochondrial mass and morphology are also central to mitochondrial function. The relevance of these mechanisms to the human vasculature in DM is unknown.
Methods: Blood mononuclear cells were isolated from 30 DM patients and 32 non-diabetics. Subcutaneous arterioles were harvested by gluteal adipose tissue biopsy in a subset (15 DM, 17 controls). ΔΨm was measured in cells and arterioles using the membrane potential-sensitive fluorescent dye JC-1. Mitochondrial mass was measured using the cardiolipin-specific fluorophore nonyl acridine orange. Endothelium dependent vasodilation was assessed using video microscopy (arterioles) and ultrasonography (brachial artery). Arteriolar vasoreactivity was also determined in the setting of low-dose (100 nM) CCCP to reduce ΔΨm magnitude.
Results: ΔΨm magnitude of the arteriolar endothelium and mononuclear cells were significantly greater in DM patients [P=0.01 (endothelium), P < 0.0001 (mononuclear cells)]. Mitochondrial mass was significantly lower in DM mononuclear cells (P=0.004), and in DM endothelium following age adjustment (P=0.003). Endothelium dependent vasodilation was impaired in DM in the brachial artery and subcutaneous arterioles (both P<0.001). CCCP treatment of the DM arteriolar endothelium reversed microvascular endothelial dysfunction (P<0.001 vs. untreated).
Conclusions: ΔΨm is hyperpolarized and mitochondrial mass is lower in the arteriolar endothelium and mononuclear cells of DM patients with endothelial dysfunction. Pharmacological normalization of ΔΨm reverses microvascular endothelial dysfunction in DM. These findings are consistent with experimental studies suggesting a link between mitochondria and vascular disease. Interventions that restore mitochondrial membrane potential and mass in DM may have therapeutic potential.