Overexpression of 12-Lipoxygenase Causes Cardiac Fibroblast Cell Growth

Wen, Yeong-Ray; Gu, Jiali; Liu, Yaxia; Wang, Ping H.; Sun, Yanyu; Nadler, Jerry L.

doi:10.1161/01.res.88.1.70

Cited by 42 publications

(24 citation statements)

References 33 publications

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“…However, p38 MAPK activation was not evaluated in those studies. Cardiac fibroblasts overexpressing 12-LO have increased p38 MAPK, which seems to mediate the increased growth in these cells (46). Lipoxygenase products can modulate calcium currents in VSMCs (47) and also induce oxidant stress and inflammatory gene expression (48,49).…”

Section: Discussionmentioning

confidence: 99%

The Oxidized Lipid and Lipoxygenase Product 12(S)-Hydroxyeicosatetraenoic Acid Induces Hypertrophy and Fibronectin Transcription in Vascular Smooth Muscle Cells via p38 MAPK and cAMP Response Element-binding Protein Activation

Reddy¹,

Thimmalapura²,

Lanting³

et al. 2002

Journal of Biological Chemistry

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124

137

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Growth factor-and cytokine-induced vascular smooth muscle cell proliferation, migration, hypertrophy, and matrix production have been shown to play important roles in the development of vascular disorders such as atherosclerosis, hypertension, and restenosis. Growth factors such as angiotensin II (AngII) 1 and platelet-derived growth factor (PDGF) activate intracellular phospholipases, leading to the formation of arachidonic acid, which can be further metabolized by cyclooxygenases, cytochrome P-450 oxygenases, and lipoxygenases (1). Lipoxygenase (LO) action leads to the formation of oxidized lipids such as 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). LOs and their products of arachidonic acid and linoleic acid metabolism have been shown to mediate growth factor effects in vascular smooth muscle cells (VSMCs) as well as responses to vascular injury. Lipoxygenases are classified as 5-, 8-, 12-, and 15-lipoxygenases based on their ability to insert molecular oxygen at the corresponding carbon atom of arachidonic acid. Three major isoforms of 12-LO have been cloned. They are platelet-type 12-LO, leukocyte-type 12-LO, and epidermis-type 12-LO. These proteins are products of distinct genes and vary in tissue distribution (2, 3).Leukocyte 12-LO has been cloned from porcine and mouse leukocytes (4, 5). The presence of leukocyte-type 12-LO (also termed 12/15-LO) has also been demonstrated in various cell types and tissues, including VSMCs, adrenal cells, rat brain, and kidney (6 -11). Studies from this and other laboratories (12-21) have implicated the leukocyte-type 12-LO pathway in the pathogenesis of atherosclerosis and restenosis. 12-LO expression was demonstrated in atherosclerotic lesions (12). In vascular and mononuclear cells, growth factors and cytokines as well as high glucose stimulate both the activity and expression of 12-LO (6, 13-15). Furthermore, expression of 12-LO protein and mRNA is markedly increased in neointima of balloon-injured rat carotid arteries, and pretreatment with LO inhibitors reduces the rate of neointimal thickening in this model (16,17). We have demonstrated that treatment with a chimeric DNA-RNA hammerhead ribozyme targeted to cleave rat leukocyte-type 12-LO mRNA significantly reduces neointimal thickening in balloon-injured rat arteries (18). We have

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Section: Discussionmentioning

confidence: 99%

The Oxidized Lipid and Lipoxygenase Product 12(S)-Hydroxyeicosatetraenoic Acid Induces Hypertrophy and Fibronectin Transcription in Vascular Smooth Muscle Cells via p38 MAPK and cAMP Response Element-binding Protein Activation

Reddy¹,

Thimmalapura²,

Lanting³

et al. 2002

Journal of Biological Chemistry

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124

137

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“…25 They are also in agreement with observations that overexpression of mouse 12/15-LO in VSMC or fibroblasts leads to increased hypertrophy and p38 MAPK activity. 25,34 Evidence suggests that 12(S)-HETE can directly induce VSMC migration 20 and 12-LO can mediate PDGF-induced chemotactic effects in VSMC. 17,22,23 In the current study, we observed that PDGF-induced migration was significantly attenuated in the LOKO cells relative to WT, thus providing in vivo relevance to the in vitro observations.…”

Section: Discussionmentioning

confidence: 99%

“…25,26 Furthermore, p38 MAPK activity was augmented in rat VSMC and cardiac fibroblasts overexpressing 12-LO cells. 25,34 Hence, we hypothesized that p38 MAPK activation may be reciprocally attenuated in LOKO VSMC. MVSMC were stimulated with serum (10% FBS) and cell lysates immunoblotted with phosphospecific-p38 MAPK antibody.…”

Section: Reduced Activation Of P38 Mapk In Loko Mvsmcmentioning

confidence: 99%

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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“…In contrast, Tanaka et al (5) showed that treating rat neonatal cardiomyocytes with IL-1␤ stimulated an increase in p38 MAPK phosphorylation that persisted for 4 h. Whereas the reasons for the apparent differences in the duration of IL-1␤-stimulated MAPKAP-K2 activation and p38 MAPK phosphorylation in these studies are unknown, these independent experimental approaches both demonstrated that the IL-1␤-stimulated increase in p38 MAPK activity preceded GIIa PLA 2 protein synthesis by IL-1␤-treated cardiomyocytes. Second, the IL-1␤-stimulated increases in MAPKAP-K2 activity, GIIa PLA 2 mRNA expression, and GIIa PLA 2 protein synthesis and release were attenuated by pretreating cardiomyocytes with SB202190, a pyridinyl imidazole that selectively constrains the activity of p38␣ and p38␤ MAPK but does not affect p42/44 MAPK or JNK activity (53,54). Third, infection with an adenovirus encoding the constitutively active form of MKK6, MKK6(Glu), the direct upstream activator of p38 MAPK, was sufficient to induce GIIa PLA 2 protein synthesis and release by cardiomyocytes in the absence of IL-1␤.…”

Section: P38 Mapk Regulates Giia Pla 2 Expression In Cardiomyocytesmentioning

confidence: 99%

p38 MAPK Regulates Group IIa Phospholipase A2Expression in Interleukin-1β-stimulated Rat Neonatal Cardiomyocytes

Dégousée¹,

Stefanski²,

Lindsay³

et al. 2001

Journal of Biological Chemistry

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Group IIa phospholipase A 2 (GIIa PLA 2 ) is released by some cells in response to interleukin-1␤. The purpose of this study was to determine whether interleukin-1␤ would stimulate the synthesis and release of GIIa PLA 2 from cardiomyocytes, and to define the role of p38 MAPK and cytosolic PLA 2 in the regulation of this process. Whereas GIIa PLA 2 mRNA was not identified in untreated cells, exposure to interleukin-1␤ resulted in the sustained expression of GIIa PLA 2 mRNA. Interleukin-1␤ also stimulated a progressive increase in cellular and extracellular GIIa PLA 2 protein levels and increased extracellular PLA 2 activity 70-fold. In addition, interleukin-1␤ stimulated the p38 MAPK-dependent activation of the downstream MAPK-activated protein kinase, MAPKAP-K2. Treatment with the p38 MAPK inhibitor, SB202190, decreased interleukin-1␤ stimulated MAPKAP-K2 activity, GIIa PLA 2 mRNA expression, GIIa PLA 2 protein synthesis, and the release of extracellular PLA 2 activity. Infection with an adenovirus encoding a constitutively active form of MKK6, MKK6(Glu), which selectively phosphorylates p38 MAPK, induced cellular GIIa PLA 2 protein synthesis and the release of GIIa PLA 2 and increased extracellular PLA 2 activity 3-fold. In contrast, infection with an adenovirus encoding a phosphorylation-resistant MKK6, MKK6(A), did not result in GIIa PLA 2 protein synthesis or release by unstimulated cardiomyocytes. In addition, infection with an adenovirus encoding MKK6(A) abrogated GIIa PLA 2 protein synthesis and release by interleukin-1␤-stimulated cells. These results provide direct evidence that p38 MAPK activation was necessary for interleukin-1␤-induced synthesis and release of GIIa PLA 2 by cardiomyocytes. Interleukin-1␤ (IL-1␤)1 has been implicated in the pathophysiology of a variety of myocardial disease states, including cardiac hypertrophy, congestive heart failure, and ischemiareperfusion injury (1-3). IL-1␤ is thought to participate in the genesis of these cardiac pathologies through the induction of specific genes, such as inducible nitric-oxide synthase, cyclooxygenase-2, matrix metalloproteinase, vascular endothelial growth factor, and ␣B-crystallin (4 -6). As the range of genes that are induced by cardiomyocytes following exposure to IL-1␤ have not been fully defined, the precise mechanisms that lead to the phenotypic changes that follow exposure to IL-1␤ remain incompletely understood.The effects of IL-1␤ in cardiomyocytes are mediated, in part, by stimulation of mitogen-activated protein kinase (MAPK) enzymes. The MAPK enzymes include p38 MAPK, p42/44 MAPK, and JNK. Molecular cloning studies have led to the identification of four distinct p38 MAPK isoforms as follows: p38␣, p38␤2, p38␥, and p38␦ (7). The MAPK enzymes exert distinct biological functions, as p38␣ MAPK promoted apoptosis, whereas p38␤2 MAPK promoted myocardial hypertrophy and cell survival (8, 9). p38 MAPK activity is increased by phosphorylation on a Thr-Gly-Tyr motif by MAPK kinases, including MKK3 and MKK6 (10,11). MKK6 forms a function...

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Overexpression of 12-Lipoxygenase Causes Cardiac Fibroblast Cell Growth

Cited by 42 publications

References 33 publications

The Oxidized Lipid and Lipoxygenase Product 12(S)-Hydroxyeicosatetraenoic Acid Induces Hypertrophy and Fibronectin Transcription in Vascular Smooth Muscle Cells via p38 MAPK and cAMP Response Element-binding Protein Activation

The Oxidized Lipid and Lipoxygenase Product 12(S)-Hydroxyeicosatetraenoic Acid Induces Hypertrophy and Fibronectin Transcription in Vascular Smooth Muscle Cells via p38 MAPK and cAMP Response Element-binding Protein Activation

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

p38 MAPK Regulates Group IIa Phospholipase A2Expression in Interleukin-1β-stimulated Rat Neonatal Cardiomyocytes

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