Oxidized LDL Induces Apoptosis in Cultured Smooth Muscle Cells: A Possible Role for 7-Ketocholesterol

Nishio, Eisuke; Arimura, Shinya; Watanabe, Yasuhiro

doi:10.1006/bbrc.1996.0907

Cited by 105 publications

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“…The slides were then rinsed with PBS for 15 min at room temperature and stained with 3,3'-diaminobenzidine tetrahydrochloride substrate solution containing 0.02% hydrogen peroxidase for 30 min at room temperature. Then slides were counterstained with methyl green for 30 s, washed in 100% butanol (Nishio et al, 1996a).…”

Section: Cell Culturementioning

confidence: 99%

The regulation of mitogenesis and apoptosis in response to the persistent stimulation of α₁‐adrenoceptors: a possible role of 15‐lipoxygenase

Nishio

Watanabe

1997

British J Pharmacology

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Activation of α1‐adrenoceptor stimulation regulates eicosanoid metabolism and growth in vascular smooth muscle cells (VSMCs). The purpose of this study was to investigate the functional implications of lipoxygenase pathway in α1‐adrenoceptor‐stimulated VSMCs growth through mutually exclusive biological functions, that is cell proliferation and cell death. Phenylephrine (10 μM), a specific α1‐adrenoceptor agonist, enhanced [3H]‐thymidine incorporation by 300% above basal. Nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, caused 36 and 50% decrease in phenylephrine (10 μM)‐stimulated [3H]‐thymidine incorporation at concentrations of 1 μM and 10 μM respectively. Inversely, treatment of phenylephrine (10 μM)‐stimulated VSMCs with NDGA induced DNA fragmentation in a dose‐dependent fashion. The level of induction of DNA fragmentation by NDGA was 225, 319 and 406% above the phenylephrine (10 μM)‐level at concentrations of 0.1 μM, 1 μM and 10 μM, respectively. This induction of DNA fragmentation was partially prevented by exogenous 15‐hydroxyeicosatetraenoic acid (15‐HETE). The inhibition of apoptosis was 53 and 63% at concentrations of 5 μM and 10 μM of 15HETE, respectively, as compared with phenylephrine (10 μM) in the presence of NDGA (10 μM). Furthermore, we performed the time‐course analysis of Bcl‐2 protein expression in phenylephrine (10 μM)‐stimulated VSMCs. The expression of Bcl‐2 protein disappeared after a 2 h incubation in the presence of NDGA (10 μM), but remained stable after a 2 h incubation period in the absence of NDGA (10 μM). These results suggest that the lipoxygenase pathway is involved in cell proliferation by preventing apoptosis through the level of Bcl‐2 protein expression.

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Section: Cell Culturementioning

confidence: 99%

The regulation of mitogenesis and apoptosis in response to the persistent stimulation of α₁‐adrenoceptors: a possible role of 15‐lipoxygenase

Nishio

Watanabe

1997

British J Pharmacology

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“…Some of the functions were clearly contradictory with each other. OxLDL stimulated cell proliferation in smooth muscle cells (Auge et al, 1995;Auge et al, 1996;Chai et al, 1996) whereas it induced cell death in endothelial cells (Quinn, et al, 1985), smooth muscle cells (Nishio et al, 1996), or macrophages (Hardwick et al, 1996). However, it was difficult to explain why the oxLDL-induced cellular responses were contrary and which major contributor resulted in those responses.…”

Section: Introductionmentioning

confidence: 99%

Oxidation-dependent effects of oxidized LDL: proliferation or cell death

Han

Pak²

1999

Exp Mol Med

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Oxidized low-density lipoprotein (oxLDL) induces a wide range of cellular responses to produce atherosclerotic lesion, but key factors determining the response are not understood. In this study, purified LDL was oxidized with copper sulfate, and its physical properties and the related biological responses were investigated. The average hydrodynamic diameter of the lightly oxidized LDL was approximately 25 nm and its Rf value relative to nLDL on agarose gel was between 1.0 and 1.25. The diameter of the extensively oxidized LDL was over 30 nm, the Rf value was over 2.0. A 24 h-exposure of resting RAW264.7 macrophage cells to 100 µ µ µ µg/ml of the lightly oxidized LDL induced proliferation and macrophage activation whereas the extensively oxidized LDL induced cell death at the same concentration. In contrast, 200 µ µ µ µg/ ml of oxLDL caused cell death regardless of oxidation degree. Short incubation (4-6 h) of the highly oxidized LDL (100 µ µ µ µg/ml) also resulted in cell proliferation. OxLDL-induced cell death showed mixed characteristics of apoptosis and/or necrosis depending on the strength and duration of the insult. These results suggest that cellular responses induced by oxLDL be dependent on the oxidation degree, the duration of exposure, and the concentration of oxLDL.

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“…Oxidation of LDL in vitro renders the molecule potentially atherogenic: ox-LDL stimulates monocyte-endothelial cell interactions, 1 induces cytokine synthesis and release from macrophages, 2,3 and is an apoptotic stimulus in smooth muscle cells. 4,5 Ox-LDL is recognized by macrophage scavenger receptors 6,7 and is a potent inducer of foam cell formation. 8 -11 Flanked by reports that ox-LDL can be immunohistochemically detected in rabbit atherosclerotic lesions, 12,13 that antibodies against ox-LDL occur in patients with atherosclerosis, 14 -17 and that antioxidants reduce the risk of myocardial infarction, 18 -22 these findings have left little room for doubt that ox-LDL is, indeed, the prime initiator of atherosclerosis.…”

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Immunohistochemical Demonstration of Enzymatically Modified Human LDL and Its Colocalization With the Terminal Complement Complex in the Early Atherosclerotic Lesion

Torzewski¹,

Klouche²,

Hock³

et al. 1998

ATVB

168

162

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Abstract-Treatment of low density lipoprotein (LDL) with degrading enzymes transforms the molecule to a moiety that is micromorphologically indistinguishable from lipoproteinaceous particles that are present in atherosclerotic plaques, and enzymatically modified LDL (E-LDL), but not oxidized LDL (ox-LDL), spontaneously activates the alternative complement pathway, as do lesion lipoprotein derivatives. Furthermore, because E-LDL is a potent inducer of macrophage foam cell formation, we propose that enzymatic degradation may be the key process that renders LDL atherogenic. In this article, we report the production of two murine monoclonal antibodies recognizing cryptic epitopes in human apolipoprotein B that become exposed after enzymatic attack on LDL. One antibody reacted with LDL after single treatment with trypsin, whereas recognition by the second antibody required combined treatment of LDL with trypsin and cholesterol esterase. In ELISAs, both antibodies reacted with E-LDL produced in vitro and with lesion complement activator derived from human atherosclerotic plaques, but they were unreactive with native LDL or ox-LDL. The antibodies stained E-LDL, but not native LDL or ox-LDL, that had been artificially injected into arterial vessel walls. With the use of these antibodies, we have demonstrated that early human atherosclerotic coronary lesions obtained at autopsy as well as lesions examined in freshly explanted hearts always contain extensive extracellular deposits of E-LDL. Terminal complement complexes, detected with a monoclonal antibody specific for a C5b-9 neoepitope, colocalized with E-LDL within the intima, which is compatible with the proposal that subendothelially deposited LDL is enzymatically transformed to a complement activator at the earliest stages in lesion development. (Arterioscler Thromb Vasc Biol. 1998;18:369-378.)

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Oxidized LDL Induces Apoptosis in Cultured Smooth Muscle Cells: A Possible Role for 7-Ketocholesterol

Cited by 105 publications

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The regulation of mitogenesis and apoptosis in response to the persistent stimulation of α₁‐adrenoceptors: a possible role of 15‐lipoxygenase

The regulation of mitogenesis and apoptosis in response to the persistent stimulation of α₁‐adrenoceptors: a possible role of 15‐lipoxygenase

Oxidation-dependent effects of oxidized LDL: proliferation or cell death

Immunohistochemical Demonstration of Enzymatically Modified Human LDL and Its Colocalization With the Terminal Complement Complex in the Early Atherosclerotic Lesion

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Oxidized LDL Induces Apoptosis in Cultured Smooth Muscle Cells: A Possible Role for 7-Ketocholesterol

Cited by 105 publications

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The regulation of mitogenesis and apoptosis in response to the persistent stimulation of α1‐adrenoceptors: a possible role of 15‐lipoxygenase

The regulation of mitogenesis and apoptosis in response to the persistent stimulation of α1‐adrenoceptors: a possible role of 15‐lipoxygenase

Oxidation-dependent effects of oxidized LDL: proliferation or cell death

Immunohistochemical Demonstration of Enzymatically Modified Human LDL and Its Colocalization With the Terminal Complement Complex in the Early Atherosclerotic Lesion

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The regulation of mitogenesis and apoptosis in response to the persistent stimulation of α₁‐adrenoceptors: a possible role of 15‐lipoxygenase

The regulation of mitogenesis and apoptosis in response to the persistent stimulation of α₁‐adrenoceptors: a possible role of 15‐lipoxygenase