Arachidonic Acid Metabolites on Renin and Vascular Smooth Muscle Cell Growth

Natarajan, Rama; Stern, Naftali; Nadler, Jerry L.

doi:10.1007/978-1-4612-0231-8_26

Cited by 7 publications

(12 citation statements)

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“…Our earlier in vitro studies indicated that the 12-LO pathway of arachidonate metabolism was induced in vascular smooth muscle cells by hyperglycaemia as well as by growth factors and cytokines [4±7]. Furthermore, the 12-LO pathway seemed to mediate the hypertrophic and chemotactic effects of high glucose, angiotensin II and platelet-derived growth factor [5,6,8]. The 12-LO products have been implicated in the increased adhesion of monocytes to endothelial cells cultured under high glucose conditions [9,10].…”

Section: Discussionmentioning

confidence: 99%

“…The 12-LO products have been implicated in the increased adhesion of monocytes to endothelial cells cultured under high glucose conditions [9,10]. The LO enzymes and their products are thought to play a role in the pathology of atherosclerosis and hypertension due to their inflammatory, growth and chemotactic properties [5,27].…”

Section: Discussionmentioning

confidence: 99%

“…Growth factors such as angiotensin II and platelet-derived growth factor-BB (PDGF), as well as inflammatory cytokines such as interleukins-1, and ±8 were potent inducers of 12-LO activity and expression in the VSMC [4±8]. Furthermore, inhibitors of 12-LO could block the growth-promoting effects of angiotensin II and high glucose as well as the chemotactic effects of PDGF in VSMC [5,6,8]. 12-LO products, such as 12-(S)-hydroxyeicosatetraenoic acid (12-HETE), have chemotactic and hypertrophic effects and also increase production of the matrix protein, fibronectin in VSMC [5,8].…”

mentioning

confidence: 99%

“…Furthermore, inhibitors of 12-LO could block the growth-promoting effects of angiotensin II and high glucose as well as the chemotactic effects of PDGF in VSMC [5,6,8]. 12-LO products, such as 12-(S)-hydroxyeicosatetraenoic acid (12-HETE), have chemotactic and hypertrophic effects and also increase production of the matrix protein, fibronectin in VSMC [5,8]. We also observed significantly more binding of monocytes to endothelial cells cultured under HG conditions [9].…”

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confidence: 99%

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Role of 12-lipoxygenase and oxidant stress in hyperglycaemia-induced acceleration of atherosclerosis in a diabetic pig model

Natarajan

Gerrity

et al. 2002

Diabetologia

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Diabetes is associated with significantly accelerated rates of atherosclerotic and hypertensive cardiovascular diseases. The cellular and molecular mechanisms are still not fully understood, mainly due to the lack of animal models that mirror the changes in human beings. Atherosclerosis involves several cell types including monocytes, vascular smooth muscle cells and endothelial cells [1]. Increased oxidant stress in these cell types has been suggested to be one key factor in atherosclerosis [2].We have recently shown that pig vascular smooth muscle cells (VSMC) cultured under high glucose (HG, 25 mmol/l) conditions to mimic the diabetic Diabetologia (2002) 45: 125±133 Role of 12-lipoxygenase and oxidant stress in hyperglycaemiainduced acceleration of atherosclerosis in a diabetic pig model Abstract Aims/hypothesis. We previously showed that vascular smooth muscle cells and endothelial cells cultured under high glucose conditions produced more 12(S)-hydroxyeicosatetraenoic acid (12-HETE), the 12-lipoxygenase (12-LO) product of arachidonate metabolism, relative to normal glucose. Because the lipoxygenase (LO) pathway has been associated with oxidant stress and the pathogenesis of atherosclerosis, we now examined 12-LO activation in vivo in a pig model of diabetes-induced accelerated atherosclerosis which displays human characteristics.Methods. The animal model was developed in pigs who were fed a normal or high fat diet and given streptozotocin injections to produce normolipemicnormoglycaemic (NLNG), normolipemic-hyperglycaemic (NLHG), hyperlipemic-normoglycaemic (HLNG) and hyperlipemic-hyperglycaemic (HLHG) pigs. Tissue samples were obtained from key arterial beds to examine 12-LO expression at 20 weeks after the pigs began their diet.Results. All HG pigs maintained threefold higher serum glucose concentrations. The HL groups developed atherosclerosis but diabetic HLHG pigs showed markedly accelerated atherosclerosis (twofold) relative to non-diabetic HLNG pigs. Immunostaining showed progressive increases in 12-LO in arteries in the order NLNG, NLHG, HLNG and HLHG. Leukocyte-type 12-LO protein (immuno-blotting) as well as mRNA expression (by competitive PCR) in abdominal and coronary arteries were significantly greater in HLHG pigs than in all the other three groups. Furthermore, increased oxidant stress was observed in monocytes from NLHG and HLNG pigs, and greatly potentiated in HLHG pigs. Conclusions/interpretation. These results are consistent with the hypothesis that 12-LO activation plays a key role in accelerated atherosclerosis due to diabetes and hyperlipemia. [Diabetologia (2002) 45: 125±133]

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Role of 12-lipoxygenase and oxidant stress in hyperglycaemia-induced acceleration of atherosclerosis in a diabetic pig model

Natarajan

Gerrity

et al. 2002

Diabetologia

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“…1,2 LOs metabolize arachidonic acid to oxidized lipids and are classified as 5-, 8-, 12-, and 15-LOs, based on the ability to insert molecular oxygen at the corresponding carbon atom of arachidonic acid. Three major functionally distinct isoforms of 12-LO, namely, platelet-type, leukocyte-type, and epidermal-type 12-LO, have been cloned.…”

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Reduced Growth Factor Responses in Vascular Smooth Muscle Cells Derived from 12/15-Lipoxygenase–Deficient Mice

et al. 2003

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Abstract-Biochemical and genetic evidence support the involvement of leukocyte-type 12/15-lipoxygenase enzyme and its products in the atherogenic process. We recently showed that products of the 12/15-lipoxygenase pathway play an important role in mediating hypertrophy, matrix protein production, and inflammatory gene expression in vascular smooth muscle cells (VSMC) through activation of mitogen activated protein kinases and key transcription factors. The current study is aimed at establishing the in vivo role of 12/15-lipoxygenase in VSMC by comparing growth factor-induced responses in VSMC derived from 12/15-lipoxygenase knockout mice versus genetic control wild-type mice. In the lipoxygenase knockout cells, 12/15-lipoxygenase protein was not expressed, and levels of its product, 12(S)-hydroxyeicosatetraenoic acid, were reduced (51% of wild type). Knockout cells exhibited significantly lower rates of growth factor-induced migration, fibronectin production, and incorporation of 3 H-thymidine and 3 H-leucine (54%, 55%, 61%, and 57% of wild type, respectively). Growth factor-induced superoxide production and p38 mitogen-activated protein kinase activation were also reduced in knockout cells. Serum-stimulated AP-1 transcription factor activation was markedly reduced (50% of wild type), whereas cAMP response element binding protein activation was abrogated in knockout cells. Furthermore, growth factor-induced mRNA expression of immediate early genes and fibronectin were also greatly reduced. These results suggest that the modulation of specific signaling pathways and growth-responsive genes may be responsible for the altered growth factor responses in the lipoxygenase knockout cells. Leukocyte-type 12-LO has a wide tissue distribution, including vascular smooth muscle cells (VSMC). 6,7 In mice, both leukocyte 12/15-LO and platelet 12-LO are expressed. 8 Studies indicate that LO inhibition reduced blood pressure in renovascular hypertensive rats. 9 Furthermore, 12(S)-HETE levels were elevated in spontaneously hypertensive rats compared with age-matched Wistar-Kyoto rats, and 12(S)-HETE directly regulated calcium signals in VSMC. 10,11 Several lines of evidence implicate 12/15-LO in the development of atherosclerosis. 12/15-LO can mediate the oxidation of LDL, 12 and the enzyme and its products have been detected in atherosclerotic lesions. 13,14 Convincing evidence comes from recent data showing that disruption of 12/15-LO in apoE Ϫ/Ϫ or LDL-R Ϫ/Ϫ mice significantly reduced atherosclerosis in these mice models. 15,16 Additionally, growth factors (GFs) such as angiotensin II (Ang II) and platelet-derived growth factor (PDGF) and cytokines such as IL-1, IL-4, and IL-8 could induce 12/15-LO activity and expression in VSMC. 7,[17][18][19] Furthermore, the 12-LO product 12(S)-HETE could induce VSMC migration and extracellular matrix production. 20,21 Ang II-induced hypertrophy as well as PDGF-induced chemotactic effects were significantly blocked by pharmacological LO inhibitors and a molecular inhibitor, 12-LO ribozyme...

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Comparison of 12-lipoxygenase expression in vascular smooth muscle cells from old normotensive Wistar-Kyoto rats with spontaneously hypertensive rats

et al. 2012

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Vascular aging and essential hypertension cause similar structural and molecular modifications in the vasculature. The 12-lipoxygenase (LO) pathway of arachidonic acid metabolism is linked to cell growth and the pathology of hypertension. Thus, elevated expression of 12-LO has been observed in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR). In the present study, we investigated the differences in 12-LO expression and activity between VSMCs from old normotensive Wistar-Kyoto rats (old WKY, 90-week old) and SHR (13-week old). The protein and mRNA expression of basal or angiotensin II (Ang II)-induced 12-LO in old WKY VSMCs were higher than those in SHR VSMCs. The degradation rate of 12-LO mRNA in old WKY VSMCs was slower than that in SHR VSMCs. However, basal or Ang II-induced 12-LO mRNAs in both old WKY and SHR VSMCs decayed more rapidly than that in young WKY (13-week old) VSMCs. Higher expression of 12-LO in old WKY VSMCs than in SHR VSMCs was correlated with the expression level of Ang II subtype 1 receptor (AT(1)R). The reduced levels of nitric oxide (NO) in old WKY and SHR VSMCs compared with young WKY VSMCs were similar, and there was no significant difference in NO production between old WKY and SHR VSMCs transfected with 12-LO siRNA. In addition, in contrast to the proliferation of SHR VSMCs, the proliferation of old WKY VSMCs was not dependent on 12-LO activation. These results suggest that the potential role of 12-LO in normotensive aging vasculature may be different from that in SHR vasculature.

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Arachidonic Acid Metabolites on Renin and Vascular Smooth Muscle Cell Growth

Cited by 7 publications

References 69 publications

Role of 12-lipoxygenase and oxidant stress in hyperglycaemia-induced acceleration of atherosclerosis in a diabetic pig model

Role of 12-lipoxygenase and oxidant stress in hyperglycaemia-induced acceleration of atherosclerosis in a diabetic pig model

Reduced Growth Factor Responses in Vascular Smooth Muscle Cells Derived from 12/15-Lipoxygenase–Deficient Mice

Comparison of 12-lipoxygenase expression in vascular smooth muscle cells from old normotensive Wistar-Kyoto rats with spontaneously hypertensive rats

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