Novel pathway of endothelin-1 and reactive oxygen species in coronary vasospasm with endothelial dysfunction.
The role of endothelial dysfunction in coronary vasospasm is controversial. We hypothesized that reactive oxygen species (ROS) and endothelin-1 (ET-1) are plausible candidates as the mediator of vasospasm is linked to endothelial dysfunction. In a pig model with repetitive endothelial injury in coronary arteries, intracoronary administration of serotonin induced a vasospasm at the endothelial injury site. The level of endothelin-converting enzyme was upregulated at that site where, upon exposure to serotonin, there were also increases in p47(phox), ROS, and ET-1 fluorescence intensities, and myosin light chain phosphorylation and RhoA activation were detected. The nicotinamide adenine dinucleotide phosphate oxidase inhibitor, apocynin, had the effect of extinguishing not only ROS but also the appearance of ET-1. The chronic blockade of endothelin type-A receptor prevented a serotonin-triggered vasospasm along with the inhibition of ROS generation and myosin light chain phosphorylation. Under the coronary artery endothelial dysfunction, ET-1 is essential for an ROS-dependent coronary vasospasm. Our findings suggest that endothelial dysfunction plays a critical role in clinically defined human Prinzmetal angina.
Saitoh
Shu-Ichi
S
First Department of Internal Medicine, Fukushima Medical University, Hikarigaoka, Fukushima, Japan. sais@fmu.ac.jp
Matsumoto
Ken
K
Kamioka
Masashi
M
Ohkawara
Hiroshi
H
Kaneshiro
Takashi
T
Ishibashi
Toshiyuki
T
Maruyama
Yukio
Y
D000098:Acetophenones / Q000494:pharmacology; D000788:Angina Pectoris, Variant / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D017023:Coronary Angiography; D003329:Coronary Vasospasm / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044022:Receptor, Endothelin A / Q000378:metabolism; D012701:Serotonin; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000098:Acetophenones; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D018994:Myosin Light Chains; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D044022:Receptor, Endothelin A; D013449:Sulfonamides; C113972:T 0201; D012701:Serotonin; C056165:acetovanillone; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D020742:rhoA GTP-Binding Protein