Induction of endothelial apoptosis by 4-hydroxyhexenal.
Lipid peroxidation and its products such as 4-hydroxy-2-nonenal (HNE) and 4-hydroxyhexenal (HHE) are known to affect redox balance during aging and various degenerative processes, including vascular dysfunction. Deterioration of the endothelial cells that line the vascular wall is known to be an underlying cause of vascular dysfunction. At present, little is known about the mechanism by which HHE induces endothelial cell death (i.e. apoptosis), although HNE-induced apoptotic cell death has been reported. The aim of this study was to determine whether apoptosis induced by HHE in endothelial cells involves peroxynitrite (ONOO(-)). Our results show that in endothelial cells HHE triggers apoptotic cell death by inducing apoptotic Bax coupled with a decrease in anti-apoptotic Bcl-2. Results show that HHE induces reactive oxygen species (ROS), nitric oxide, and ONOO(-) generation, leading to redox imbalance. Furthermore, the antioxidant N-acetyl cysteine, ROS scavenger, and penicillamine, an ONOO(-) scavenger, were found to block HHE-mediated apoptosis. We used confocal laser microscopy to estimate the ability of these inhibitors to attenuate HHE-induced intracellular ONOO(-) levels thus confirming the oxidative mediation of apoptosis in endothelial cells. These findings strongly suggest that accumulated HHE triggers reactive species-mediated endothelial apoptosis, leading to vascular dysfunction as well as vascular aging. During aging, increased lipid peroxidation and its associated production of HHE may exacerbate the weakened redox balance, leading to various chronic degenerative processes including vascular dysfunction.
Lee
Ji Young
JY
Genetic Engineering Research Institute, Pusan National University, Busan, Korea.
Je
Jeong Hwan
JH
Kim
Dae Hyun
DH
Chung
Sang Woon
SW
Zou
Yani
Y
Kim
Nam Deuk
ND
Ae Yoo
Mie
M
Suck Baik
Hyung
H
Yu
Byung Pal
BP
Chung
Hae Young
HY
D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D015227:Lipid Peroxidation; D008297:Male; D018613:Microscopy, Confocal; D009569:Nitric Oxide / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010396:Penicillamine / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000494:pharmacology; D011467:Prostate / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species
D000447:Aldehydes; D016877:Oxidants; D017382:Reactive Oxygen Species; C063409:4-hydroxyhexenal; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D010396:Penicillamine