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KMID : 1011420220270010089
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Journal of Korean Ophthalmic Optics Society
2022 Volume.27 No. 1 p.89 ~ p.95
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5-Lipoxygenase Mediates Vascular Smooth Muscle Cell Depolarization Induced by 4-hydroxynonenal
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Lee Ji-Young
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Abstract
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Purpose: Retinal neovascularization (NV) is a vision-threatening complication of ischemic retinopathy that develops in various retinal disorders including diabetic retinopathy. To better understand how retinal neovasculari-zation through 4- hydroxynonenal (HNE)-mediated oxidative stress results in a wide range of biological effects, we determined whether the activation of lipoxygenase (LO) by HNE is mediated by reactive oxygen species (ROS) in vascular smooth muscle cells (VSMCs).
Methods: A10 cells were incubated with DMEM (0.5% FBS) containing HNE after preincubated for 30 min with various inhibitors. Data were analyzed by flow cytometry and western blot analysis.
Results: High levels of HNE (30 M) induced ROS formation and altered the mitochondrial membrane potential (ΔΨm), ultimately leading to VSMC apoptosis. Pretreatment with nordihydroguaiaretic acid (LO inhibitor), AA 861 (5-LO inhibitor), and baicalin (12- LO inhibitor) prevented HNE-induced ROS generation. AA 861 also blocked the loss of ΔΨm, indicating that LO is closely involved in mitochondria-derived ROS production, thereby leading to apoptosis. At low levels of HNE (1 mM), 5-LO gene expression increased.
Conclusions: These findings suggest that 5-LO mediates HNE-induced VSMC apoptosis by triggering mitochondrial dysfunction and activation by ROS excessive generation leading to the deterioration of vasculature homeostasis and subsequent vascular dysfunction, including retinal NV.
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KEYWORD
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4-Hydroxynonenal, Lipoxygenase, Mitochondrial depolarization, ROS, Retinal neovascularization
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