Abstract 11505: Increased Mitochondrial Fission Plays a Critical Role in Low Glucose-Induced Endothelial Dysfunction
Introduction: Intensive glucose control in patients with Type 2 Diabetes Mellitus has resulted in increased incidence of hypoglycemia, often with elevated risk of adverse cardiovascular events. Studies of endothelial cells (ECs) and human arterioles exposed to a low glucose (LG) environment suggest the risk is mediated through a dysfunctional endothelium, characterized by greater reactive oxygen species (ROS) production and decreased nitric oxide (NO).
Hypothesis: We propose that LG-induced endothelial dysfunction is driven by an imbalance in the fission/fusion process of mitochondrial networks within ECs.
Methods: Human ECs were used to quantify mitochondrial fission and evaluate Mdivi-1, a fission inhibitor, following incubation in either LG (40 mg/dL) or normal glucose (NG, 90 mg/dL) physiologic environments for 2 hours. Similarly, human subcutaneous adipose arterioles subjected to either LG or NG, were used to detect ROS with MitoSOX and NO with DAF-2DA, ±Mdivi-1. Arteriole vasoactivity was measured ±Mdivi-1 in a dose-response manner to acetylcholine (Ach). This experiment was repeated employing siRNA to knockdown expression of the primary fission protein, Drp1.
Results: More mitochondrial fragmentation was observed in ECs exposed to LG (LG vs NG: 3.2±0.6 vs 2.4 ±0.5, P<0.05) and was attenuated by Mdivi-1 (P<0.05). Vessels displayed increased ROS when exposed to LG (LG vs NG: 119.8±24.5 vs 80.1±21.8, P<0.02) and levels decreased with Mdivi-1 (P=0.005). Available NO decreased in LG treated vessels (LG vs NG: 19.3±2.7 vs 31.7±3.2, P<0.001) and improved with LG+Mdivi-1 (P<0.05). LG exposed vessels displayed impaired endothelial dependent vasodilation and co-incubation with Mdivi-1 rescued the dilation response (LG vs LG+Mdivi-1 at [Ach] x10-7 to 10-5 M, P<0.02). Likewise, knockdown of Drp1 also improved vasoactive response in the LG group (LG+scramble vs LG+siDrp1 at [Ach] x10-7 to 10-5 M, P<0.003).
Conclusion: Human arterioles exposed to LG conditions exhibit a decrease in NO, increased ROS and an impaired vasodilatory response correlating with dynamic mitochondrial changes. The role of the mitochondria in LG-induced endothelial dysfunction appears to be rooted in an increased mitochondrial fission response.
Author Disclosures: M.J. Tanner: None. J. Wang: None. R. Ying: None. M. Malik: None. A. Branum: None. T.B. Suboc: None. A. Coulliard: None. M.E. Widlansky: Research Grant; Significant; Merck Sharp & Dohme Corp..
- © 2015 by American Heart Association, Inc.