4-Hydroxynonenal induces vascular smooth muscle cell apoptosis through mitochondrial generation of reactive oxygen species.
4-Hydroxynonenal (HNE), an end-product of membrane lipid peroxidation, has been suggested to mediate a number of oxidative stress-linked pathological events such as cellular apoptosis. However, little is known about the signals by which HNE induces vascular smooth muscle cell (VSMC) apoptosis. To elucidate the mechanism(s) involved in HNE-induced VSMC apoptosis, we investigated the importance of mitochondria as a potential source for reactive oxygen species (ROS). Exposure of VSMC to HNE (1-30 microM) showed an augmented apoptotic changes in a concentration-dependent manner in association with an increased production of ROS, both of which were significantly attenuated by mitochondrial inhibitors such as rotenone (0.1 microM) and stigmatellin (0.1 microM), but not affected by other oxidase inhibitors involving NADPH oxidase, xanthine oxidase and cyclooxygenase. In connection with these results, HNE-induced ROS generation was not observed in mitochondrial function-deficient (rho 0) VSMC. Taken together, these results suggest that mitochondrial dysfunction plays a key role in mediating HNE-induced VSMC apoptosis through an increased mitochondrial production of ROS.
Lee
Ji Young
JY
Department of Pharmacology, College of Medicine, Pusan National University, 10 Ami-Dong 1-Ga, Seo-Gu, Busan, Republic of Korea.
Jung
Geun Young
GY
Heo
Hye Jin
HJ
Yun
Mi Ran
MR
Park
Ji Young
JY
Bae
Sun Sik
SS
Hong
Ki Whan
KW
Lee
Won Suk
WS
Kim
Chi Dae
CD
D000447:Aldehydes / Q000494:pharmacology*; D000963:Antimetabolites / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D007211:Indoles; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014475:Uncoupling Agents / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D000447:Aldehydes; D000963:Antimetabolites; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007211:Indoles; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; C007293:DAPI; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; C027576:4-hydroxy-2-nonenal