Linoleic acid and its metabolites, hydroperoxyoctadecadienoic acids, stimulate c-Fos, c-Jun, and c-Myc mRNA expression, mitogen-activated protein kinase activation, and growth in rat aortic smooth muscle cells.

Rao, Gadiparthi N.; Alexander, R. Wayne; Runge, M S

doi:10.1172/jci118130

Cited by 136 publications

(54 citation statements)

References 37 publications

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“…Indeed, lyso-PtdCho, and linoleic and oleic acids and their combinations markedly increased the mitogenic activity of VSMC. We used conventional concentrations of the above products of hydrolysis of lipoproteins (Bandyopadhyay et al, 1987;Keler et al, 1992;Rao et al 1995;Wang et al 1991), but their concentrations in the vascular wall are not known presently, and therefore their relative in vivo impact cannot be estimated.…”

Section: Lipoprotein Effect On Smooth Muscle Cellsmentioning

confidence: 99%

Mitogenic Effect of Lipoproteins on Human Vascular Smooth Muscle Cells: The Impact of Hydrolysis by gr II A Phospholipase A2

Pruzanski

Stefanski

Kopilov

et al. 2001

Laboratory Investigation

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SUMMARY:Multifactorial interaction among lipoproteins, vascular wall cells, and inflammatory mediators has been recognized as the basis of atherogenesis. In the arterial wall high-density lipoprotein (HDL) and human secretory phospholipase A 2 (sPLA 2 ) colocalize with vascular smooth muscle cells and concentrate in the atherosclerotic lesions. It has been shown that gr IIA sPLA 2 hydrolyzes lipoproteins, altering their structure and releasing active agents such as lyso-phosphatidylcholine (PtdCho) and free fatty acids. We investigated the impact of normal HDL 3 (NHDL 3 ), acute phase HDL 3 (APHDL 3 ), and low-density lipoprotein (LDL), both unhydrolyzed and sPLA 2 -hydrolyzed, and some products of hydrolysis, such as lyso-PtdCho, oleic and linoleic acid, on [ 3 H] thymidine incorporation by DNA of cultured human vascular smooth muscle cells (VSMC). NHDL 3 markedly enhanced mitogenic activity of VSMC in a dose-and time-dependent manner. Doubling of thymidine incorporation was usually achieved by 40 g/ml of NHDL 3 after 4 hours of incubation. APHDL 3 had invariably a stronger inducing effect on the mitogenic activity than NHDL 3 ; 40 g/ml more than tripled [ 3 H] thymidine incorporation after 4 hours of incubation. NHDL 3 preincubated with human apo serum amyloid A apolipoprotein-induced higher mitogenic activity in VSMC than NHDL 3 alone. Hydrolysis of NHDL 3 , APHDL 3 , or LDL by gr IIA sPLA 2 markedly enhanced mitogenic activity of VSMC as compared with unhydrolyzed lipoproteins. sPLA 2 concentrations that can be found in atherosclerotic vascular walls markedly enhanced lipoprotein-induced mitogenic activity of VSMC. sPLA 2 per se did not affect thymidine incorporation and VSMC did not release sPLA 2 into the medium. There was no evidence for hydrolysis of the wall of VSMC by gr IIA sPLA 2 . The presence of the products of hydrolysis of lipoproteins such as oleic and linoleic acids and lyso-PtdCho or their combinations with NHDL 3 explains in part markedly enhanced mitogenic activity of VSMC. It is conceivable that sPLA 2, which is known to colocalize with lipoproteins in the vascular wall in the domain of VSMC, is capable of induction of the mitogenic activity in these cells in vivo and should be considered as a proatherogenic enzyme. (Lab Invest 2001, 81:757-765).A therosclerosis is the end stage of a complex interaction of several types of vascular wall resident and infiltrating cells, lipoproteins, and a variety of inflammatory mediators (Daugherty, 1997;Libby et al, 1997;Steinberg and Witztum, 1990). Recently, substantial evidence has accumulated indicating that proinflammatory and immunologic factors play an important role in atherogenesis (Hajjar and Pomerantz 1992;Hansson et al, 1989;Nilsson, 1993;Wick et al, 1995Wick et al, , 1997. It was found that acute phase markedly influences the structure of lipoproteins (Malle et al, 1993;Pruzanski et al, 1998Pruzanski et al, , 2000 and their functions (Kisilevsky and Subrahmanyan, 1992;Shephard et al, 1987;Van Lenten et al, 1995). In acute phase (Baumann and ...

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Section: Lipoprotein Effect On Smooth Muscle Cellsmentioning

confidence: 99%

Mitogenic Effect of Lipoproteins on Human Vascular Smooth Muscle Cells: The Impact of Hydrolysis by gr II A Phospholipase A2

Pruzanski

Stefanski

Kopilov

et al. 2001

Laboratory Investigation

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“…There are contradictory ®ndings regarding the e ects of free fatty acids on VSMC growth. Some investigators have observed growth stimulation (Hu et al, 1998;Lu et al, 1996;Rao et al, 1995) while others suppression (Huttner et al, 1977;Olsson et al, 1999). In short, it has been shown (Rao et al, 1995) that a weak increase in DNA synthesis and a moderate increase in VSMC number occur after a 96 h incubation with 20 mM linoleic acid.…”

Section: Introductionmentioning

confidence: 99%

“…Some investigators have observed growth stimulation (Hu et al, 1998;Lu et al, 1996;Rao et al, 1995) while others suppression (Huttner et al, 1977;Olsson et al, 1999). In short, it has been shown (Rao et al, 1995) that a weak increase in DNA synthesis and a moderate increase in VSMC number occur after a 96 h incubation with 20 mM linoleic acid. Similarly, others (Lu et al, 1996; have found that oleic acid at concentrations from 25 ± 200 mM signi®cantly increased [ 3 H]-thymidine uptake and cell number in rat VSMC after a 6 day stimulation period.…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, others found that exposure of human arterial smooth muscle cells to 100 ± 300 mM linoleic acid lowered their proliferation rate and altered cell morphology . Moreover, it has been described that oleic acid (Lu et al, 1996; and linoleic acid (Hu et al, 1998;Rao et al, 1995) stimulate the extracellular response kinases 1 and 2 (ERK1/2, also known as p44 mapk /p42 mapk ) but not the p38 mitogen-activated protein (MAP) kinase (Lu et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Effects of authentic and VLDL hydrolysis‐derived fatty acids on vascular smooth muscle cell growth

Gouni‐Berthold

Berthold²,

Seul

et al. 2001

British J Pharmacology

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1 There are contradictory ®ndings regarding the e ects of free fatty acids on vascular smooth muscle cell (VSMC) growth. In the present study we investigated the e ects of fatty acids released from hydrolysis of human VLDL triglycerides by lipoprotein lipase and of the fatty acids most abundant in the hydrolysed VLDL, namely oleic, linoleic, palmitic and myristic acid, all non albumin-bound, on VSMC growth.2 The e ect of fatty acids on VSMC growth was assessed by [ 3 H]-thymidine incorporation, colourimetrically, by cell counting, by determination of the cytoplasmic histone-associated DNA fragments and the caspase 3 activity. The fatty acid concentrations were determined by gas chromatography-mass spectrometry. Stimulation of ERK1/2 and p38 was determined by the chemiluminescence Western blotting method. 3 Incubation of VSMC with puri®ed VLDL (100 mg ml 71 ) and lipoprotein lipase (35 u ml 71 ) led to almost complete cell death although the ERK1/2 and the p38 MAP kinases were stimulated. The EC 50 of oleic, linoleic, myristic and palmitic acid were 4.6+1.3, 2.4+0.2, 116+10 and 287+30 mM, respectively. The estimated EC 50 of myristic and palmitic acid when derived from hydrolysed VLDL were 10 and 8 times, respectively, lower than when used alone. Apoptosis was not involved in the fatty acid-induced VSMC growth suppression/death. 4 We conclude that (a) non albumin-bound fatty acids cause VSMC necrosis in a dose-dependent manner with a parallel ERK1/2 and p38 stimulation, (b) unsaturated fatty acids are more toxic to VSMC than saturated, and (c) saturated fatty acids are more toxic to VSMC in the hydrolysed VLDL than when used individually.

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“…13-Hydroperoxy-9,11-octadecadienoic acid (HPODE) and 13-hydroperoxy-10,12-octadecadienoic acid (HODE) are the oxidized products of linoleic acid, the major oxidizable fatty acid in LDL, and have been detected in oxidized LDL and atherosclerotic plaques (17,46). HPODE is known to regulate the expression of catalase, ICAM, heme oxygenase-1, endothelial nitric oxide synthase, and perlecan and is a recognized smooth muscle cell (SMC) mitogen (1,13,33,(41)(42)(43). We report that expression of syndecan-4 mRNA and protein in vascular SMC (VSMC) is controlled by HPODE using a signaling pathway that is dependent on both intracellular hydrogen peroxide generation and the activation of p42/p44 MAPK.…”

mentioning

confidence: 99%

Oxidized linoleic acid regulates expression and shedding of syndecan-4

Houston

Julien

Parthasarathy³

et al. 2005

American Journal of Physiology-Cell Physiology

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Syndecan-4, a heparan sulfate proteoglycan that is widely expressed in the vascular wall and as a cell surface receptor, modulates events relevant to acute tissue repair, including cell migration and proliferation, cell-substrate interactions, and matrix remodeling. While syndecan-4 expression is regulated in response to acute vascular wall injury, its regulation under chronic proatherogenic conditions such as those characterized by prolonged exposure to oxidized lipids has not been defined. In this investigation, arterial smooth muscle cells were treated with 13-hydroperoxy-9,11-octadecadienoic acid (HPODE) and 13-hydroperoxy-10,12-octadecadienoic acid, oxidized products of linoleic acid, which is the major oxidizable fatty acid in LDL. Both oxidized fatty acids induced a dose-dependent, rapid upregulation of syndecan-4 mRNA expression that was not attenuated by cycloheximide. This response was inhibited by pretreatment with N-acetylcysteine, catalase, or MEK1/2 inhibitors, but not by curcumin or lactacystin, known inhibitors of NF-κB. These data suggest that oxidized linoleic acid induces syndecan-4 mRNA expression through the initial generation of intracellular hydrogen peroxide with subsequent activation of the extracellular signal-regulated kinase signaling pathway via MEK1/2. Notably, the HPODE-induced enhancement of syndecan-4 mRNA was accompanied by accelerated shedding of syndecan-4. In principle, alterations in both the cell surface expression and shedding of syndecan-4 may augment a variety of proatherogenic events that occur in response to oxidized lipids.

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Linoleic acid and its metabolites, hydroperoxyoctadecadienoic acids, stimulate c-Fos, c-Jun, and c-Myc mRNA expression, mitogen-activated protein kinase activation, and growth in rat aortic smooth muscle cells.

Cited by 136 publications

References 37 publications

Mitogenic Effect of Lipoproteins on Human Vascular Smooth Muscle Cells: The Impact of Hydrolysis by gr II A Phospholipase A2

Mitogenic Effect of Lipoproteins on Human Vascular Smooth Muscle Cells: The Impact of Hydrolysis by gr II A Phospholipase A2

Effects of authentic and VLDL hydrolysis‐derived fatty acids on vascular smooth muscle cell growth

Oxidized linoleic acid regulates expression and shedding of syndecan-4

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