Dynamin-related protein 1 mediates low glucose-induced endothelial dysfunction in human arterioles. Am J Physiol Heart Circ Physiol 2017 Mar 01;312(3):H515-H527
Date
12/08/2016Pubmed ID
27923790Pubmed Central ID
PMC5402007DOI
10.1152/ajpheart.00499.2016Scopus ID
2-s2.0-85014447139 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
Intensive glycemic regulation has resulted in an increased incidence of hypoglycemia. Hypoglycemic burden correlates with adverse cardiovascular complications and contributes acutely and chronically to endothelial dysfunction. Prior data indicate that mitochondrial dysfunction contributes to hypoglycemia-induced endothelial dysfunction, but the mechanisms behind this linkage remain unknown. We attempt to determine whether clinically relevant low-glucose (LG) exposures acutely induce endothelial dysfunction through activation of the mitochondrial fission process. Characterization of mitochondrial morphology was carried out in cultured endothelial cells by using confocal microscopy. Isolated human arterioles were used to explore the effect LG-induced mitochondrial fission has on the formation of detrimental reactive oxygen species (ROS), bioavailability of nitric oxide (NO), and endothelial-dependent vascular relaxation. Fluorescence microscopy was employed to visualize changes in mitochondrial ROS and NO levels and videomicroscopy applied to measure vasodilation response. Pharmacological disruption of the profission protein Drp1 with Mdivi-1 during LG exposure reduced mitochondrial fragmentation among vascular endothelial cells (LG: 0.469; LG+Mdivi-1: 0.276; P = 0.003), prevented formation of vascular ROS (LG: 2.036; LG+Mdivi-1: 1.774; P = 0.005), increased the presence of NO (LG: 1.352; LG+Mdivi-1: 1.502; P = 0.048), and improved vascular dilation response to acetylcholine (LG: 31.6%; LG+Mdivi-1; 78.5% at maximum dose; P < 0.001). Additionally, decreased expression of Drp1 via siRNA knockdown during LG conditions also improved vascular relaxation. Exposure to LG imparts endothelial dysfunction coupled with altered mitochondrial phenotypes among isolated human arterioles. Disruption of Drp1 and subsequent mitochondrial fragmentation events prevents impaired vascular dilation, restores mitochondrial phenotype, and implicates mitochondrial fission as a primary mediator of LG-induced endothelial dysfunction.NEW & NOTEWORTHY Acute low-glucose exposure induces mitochondrial fragmentation in endothelial cells via Drp1 and is associated with impaired endothelial function in human arterioles. Targeting of Drp1 prevents fragmentation, improves vasofunction, and may provide a therapeutic target for improving cardiovascular complications among diabetics.Listen to this article's corresponding podcast @ http://ajpheart.podbean.com/e/mitochondrial-dynamics-impact-endothelial-function/.
Author List
Tanner MJ, Wang J, Ying R, Suboc TB, Malik M, Couillard A, Branum A, Puppala V, Widlansky MEAuthor
Michael E. Widlansky MD Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Arterioles
Dynamins
Endothelium, Vascular
Energy Metabolism
Female
GTP Phosphohydrolases
Gene Knockdown Techniques
Glucose
Human Umbilical Vein Endothelial Cells
Humans
Male
Membrane Potential, Mitochondrial
Microtubule-Associated Proteins
Middle Aged
Mitochondria, Heart
Mitochondrial Proteins
Nitric Oxide
Quinazolinones
RNA, Small Interfering
Reactive Oxygen Species
Vascular Diseases
Vasodilation
