Inhibition of angiotensin-converting enzyme protects endothelial cell against hypoxia/reoxygenation injury.
Cardiovascular tissue injury in ischemia/reperfusion has been shown to be prevented by angiotensin-converting enzyme (ACE) inhibitors. However, the mechanism on endothelial cells has not been assessed in detail. Cultured human aortic endothelial cells (HAEC) were exposed to hypoxia with or without reoxygenation. Hypoxia enhanced apoptosis along with the activation of caspase-3. Reoxygenation increased lactate dehydrogenase release time-dependently, along with an increase of intracellular oxygen radicals. ACE inhibitor quinaprilat and bradykinin significantly lessened apoptosis and lactate dehydrogenase release with these effects being diminished by a kinin B2 receptor antagonist and a nitric oxide synthase inhibitor. In conclusion, hypoxia activated the suicide pathway leading to apoptosis of HAEC by enhancing caspase-3 activity, while subsequent reoxygenation induced necrosis by enhancing oxygen radical production. Quinaprilat could ameliorate both apoptosis and necrosis through the upregulation of constitutive endothelial nitric oxide synthase via an increase of bradykinin, with the resulting increase of nitric oxide.
First Department of Internal Medicine, Kyoto Prefectural University of Medicine, Japan.
N
N
Fujita
H
H
Manabe
N
N
Yoshida
N
N
Matsumoto
J
J
Ochiai
Y
Y
Masui
M
M
Uemura
Y
Y
Naito
T
T
Yoshikawa
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001011:Aorta; D017209:Apoptosis; D001920:Bradykinin / Q000378:metabolism / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010100:Oxygen / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control; D044005:Tetrahydroisoquinolines
D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D017382:Reactive Oxygen Species; D044005:Tetrahydroisoquinolines; D009569:Nitric Oxide; C054501:quinaprilat; D007770:L-Lactate Dehydrogenase; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D010100:Oxygen; D001920:Bradykinin