title: Optimal reactive oxygen species concentration and p38 MAP kinase are required for coronary collateral growth.
abstract: Reactive oxygen species (ROS) are implicated in coronary collateral growth (CCG). We evaluated the requirement for ROS in human coronary artery endothelial cell (HCAEC) tube formation, CCG in vivo, and signaling (p38 MAP kinase) by which ROS may stimulate vascular growth. The flavin-containing oxidase inhibitor diphenyleneiodonium (DPI) or the superoxide dismutase inhibitor diethyldithiocarbamate (DETC) blocked vascular endothelial growth factor-induced HCAEC tube formation in Matrigel. We assessed the effect of DPI and DETC on CCG in a rat model of repetitive ischemia (RI) (40 s left anterior descending coronary artery occlusion every 20 min for 2 h 20 min, 3 times/day, 10 days). DPI or DETC was given intraperitoneally, or the NAD(P)H oxidase inhibitor apocynin was given in drinking water. Collateral-dependent flow (measured by using microspheres) was expressed as a ratio of normal and ischemic zone flows. In sham-operated rats, collateral flow in the ischemic zone was 18 +/- 6% of normal zone; in the RI group, collateral flow in the ischemic zone was 83 +/- 5% of normal zone. DPI prevented the increase in collateral flow after RI (25 +/- 4% of normal zone). Similar results were obtained with apocynin following RI (32 +/- 7% of that in the normal zone). DETC achieved similar results (collateral flow after RI was 21 +/- 2% of normal zone). DPI and DETC blocked RI-induced p38 MAP kinase activation in response to vascular endothelial growth factor and RI. These results demonstrate a requirement for optimal ROS concentration in HCAEC tube formation, CCG, and p38 MAP kinase activation. p38 MAP kinase inhibition prevented HCAEC tube formation and partially blocked RI-induced CCG (42 +/- 7% of normal zone flow), indicating that p38 MAP kinase is a critical signaling mediator of CCG.
authors.affiliation: Department of Physiology, Louisiana State Univeristy Health Sciences Center, New Orleans, Louisiana, USA. procic@neoucom.edu
authors.forename: Petra
authors.initials: P
authors.lastname: Rocic
authors.forename: Christopher
authors.initials: C
authors.lastname: Kolz
authors.forename: Ryan
authors.initials: R
authors.lastname: Reed
authors.forename: Barry
authors.initials: B
authors.lastname: Potter
authors.forename: William M
authors.initials: WM
authors.lastname: Chilian
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001783:Blood Flow Velocity; D002478:Cells, Cultured; D003097:Collateral Circulation / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000601:surgery; D004195:Disease Models, Animal; D004050:Ditiocarb / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008026:Ligation; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018919:Neovascularization, Physiologic; D009861:Onium Compounds / Q000494:pharmacology; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000098:Acetophenones; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009861:Onium Compounds; D011725:Pyridines; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; C007517:diphenyleneiodonium; D004050:Ditiocarb; C056165:acetovanillone; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580