The key role of transforming growth factor-beta receptor I and 15-lipoxygenase in hypoxia-induced proliferation of pulmonary artery smooth muscle cells

Liu, Yun; Ma, Cui; Zhang, Qianlong; Yu, Lei; Ma, Jun; Zhang, Lei; Hao, Xuewei; Cao, Fangyuan; Wang, Lin; Zhu, Daling

doi:10.1016/j.biocel.2012.04.009

Cited by 37 publications

(41 citation statements)

References 26 publications

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“…Similarly, we have reported that overexpression of 15-LO1 or 15-LO2 exacerbates restenosis in response to injury (49,50). In addition, the previous studies by us as well as others have reported the presence of 15-LO or its inhibitor, nordihydroguaiaretic acid-sensitive production of 15(S)-HETE and 13(S)-hydroxyoctadecadienoic acid in response to incubation with AA and linoleic acid, respectively, in both vascular smooth muscle cells and endothelial cells (28,(51)(52)(53)(54). Thus, all these reports may lend support to the role of 15-LO-15(S)-HETE axis in vascular diseases.…”

Section: Discussionmentioning

confidence: 81%

Vascular Endothelial Tight Junctions and Barrier Function Are Disrupted by 15(S)-Hydroxyeicosatetraenoic Acid Partly via Protein Kinase Cϵ-mediated Zona Occludens-1 Phosphorylation at Threonine 770/772

Chattopadhyay

Dyukova

Singh

et al. 2014

Journal of Biological Chemistry

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Background: Tight junctions play an essential role in the maintenance of endothelial barrier function. Results: 15(S)-HETE stimulated ZO-1 phosphorylation at Thr-770/772 residues in PKC⑀-dependent MEK1-ERK1/2 activation disrupting endothelial tight junctions and barrier function. Conclusion: PKC⑀ by interrupting ZO-1 and occludin interactions plays a role in 15(S)-HETE-induced endothelial TJ disruption. Significance: 12/15-Lipoxygenase appears to be a crucial player in the modulation of endothelial barrier permeability.

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Section: Discussionmentioning

confidence: 81%

Vascular Endothelial Tight Junctions and Barrier Function Are Disrupted by 15(S)-Hydroxyeicosatetraenoic Acid Partly via Protein Kinase Cϵ-mediated Zona Occludens-1 Phosphorylation at Threonine 770/772

Chattopadhyay

Dyukova

Singh

et al. 2014

Journal of Biological Chemistry

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“…In fact, various transcript factors and growth factors, such as GATA, early growth response 1, cAMP response element-binding protein, platelet-derived growth factor, and transforming growth factor-β1, have been shown previously to be associated with 15-LO regulation under other conditions. [26][27][28][29] In contrast, actinomycin D and NF-κB inhibitors have similar effects on the 15-LO-2 expression, which suggests different regulation mechanisms of 15-LO-1 and 15-LO-2.…”

Section: Discussionmentioning

confidence: 99%

15-Lipoxygenase Promotes Chronic Hypoxia–Induced Pulmonary Artery Inflammation via Positive Interaction With Nuclear Factor-κB

Rao²,

Liu³

et al. 2013

ATVB

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Objective-Our laboratory has previously demonstrated that 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) is involved in hypoxic pulmonary arterial hypertension. Chronic hypoxia-induced vascular inflammation has been considered as an important stage in the development of pulmonary arterial hypertension. Here, we determined the contribution of 15-HETE in the hypoxia-induced pulmonary vascular inflammation. Approach and Results-Chronic hypoxia-induced monocyte/macrophage infiltration and the expressions of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were analyzed in hypoxic rat model and cultured pulmonary arterial endothelium cells using immunochemistry methods. We found that monocyte/macrophage infiltration and the expressions of intercellular adhesion molecules under hypoxia were markedly inhibited by 15-HETE inhibitors or 15-LO1/2 small interfering RNA. In addition, exogenous 15-HETE enhanced the expression of both adhesion molecules in pulmonary arterial endothelium cells in a time-dependent manner. Hypoxia-induced 15-LO1/2 expression in rat pulmonary arterial endothelium cells was significantly abolished by nuclear factor-κB inhibitors. Meanwhile, nuclear factor-κB activity was enhanced prominently by the 15-LO1/2 product, 15-HETE, suggesting a positive feedback mechanism. Conclusions-Taken together, our results suggest that chronic hypoxia promotes monocyte infiltration into the vasculature and adhesion molecules upregulation in pulmonary arterial endothelium cells via a positive interaction between 15-LO/15-HETE and nuclear factor-κB. Our study revealed a novel mechanism underlying hypoxia-induced pulmonary arterial inflammation and suggested new therapeutic strategies targeting 15-LO/15-HETE and nuclear factor-κB in the treatment of pulmonary arterial hypertension. (Arterioscler Thromb Vasc Biol. 2013;33:971-979.)

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“…In another study, Sakao et al (6) reported that the apoptosis of endothelial cells induces the release of mediators, in particular TGF-β1, which activates the proliferation and migration of vascular smooth muscle cells. Liu et al (40) showed that TGF-β1 increased the progression of cells from the G0/G1 phase to the G2/M + S phase and regulated the cell cycle progression of PASMCs. Considerable experimental evidence suggests that TGF-β1 mediates human PASMC proliferation in persistent hypoxia-induced PAH (41).…”

Section: Discussionmentioning

confidence: 99%

EETs and CYP2J2 inhibit TNF-α-induced apoptosis in pulmonary artery endothelial cells and TGF-β1-induced migration in pulmonary artery smooth muscle cells

Feng

Zhao

et al. 2013

International Journal of Molecular Medicine

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Abstract. Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids (EETs) have multiple biological functions in cardiovascular homeostasis. The anti-inflammatory, anti-migratory and pro-proliferative effects of EETs suggest a possible beneficial role for EETs in the apoptosis, proliferation and migration of pulmonary vascular cells. In this study, we investigated the effects of exogenous EETs and cytochrome P450 2J2 (CYP2J2) overexpression on tumor necrosis factor-α (TNF-α)-induced pulmonary artery endothelial cell (PAEC) apoptosis, and transforming growth factor-β1 (TGF-β1)-induced pulmonary artery smooth muscle cell (PASMC) proliferation and migration. PAECs and PASMCs were cultured from porcine pulmonary arteries. Our findings indicated that EETs or CYP2J2 overexpression significantly protected the PAECs from TNF-α-induced apoptosis, as evaluated by cell viability and flow cytometry. Two mechanisms were found to be involved in these important protective effects: firstly, EETs and CYP2J2 overexpression inhibited the decrease in the expression of the antiapoptotic proteins, Bcl-2 and Bcl-xL, as well as the increase in the expression of the pro-apoptotic protein, Bax, mediated by TNF-α; secondly, they activated the phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) signaling pathways. We also found that 11,12-EET and 14,15-EET significantly inhibited TGF-β1-stimulated PASMC migration. However, EETs did not suppress TGF-β1-induced PASMC proliferation in vitro. These data may represent a novel approach to mitigate pulmonary vascular remodeling in diseases, such as pulmonary arterial hypertension. IntroductionPulmonary vascular remodeling is one of the most important pathological changes in patients with pulmonary arterial hypertension (PAH). Endothelial cells are recognized as major regulators of vascular function. The balance between endothelial cell survival and death is critical in various processes, such as the regulation of vasoconstriction and vasodilation, smooth muscle cell growth and migration, thrombotic formation, intravascular inflammation and vascular remodeling (1,2). Inflammation is one of the main features of PAH, and circulating levels of cytokines, including tumor necrosis factor-α (TNF-α), are elevated in patients with PAH (3,4). During the early stages of vascular remodeling, inflammatory infiltration directly participates in the apoptosis of endothelial cells. Considerable experimental evidence suggests that the apoptosis of endothelial cells induces the release of mediators, in particular, transforming growth factor-β1 (TGF-β1), which induces the proliferation and migration of vascular smooth muscle cells (5,6). Sturrock et al (7) demonstrated that TGF-β1 is abundantly expressed in patients with pulmonary hypertension, and promotes pulmonary artery smooth muscle cell (PASMC) proliferation in low serum medium. The inhibition of TGF-β1 signaling has been demonstrated to attenuate pulmonary vascular remodeling and increase right ventricular pressure in anim...

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The key role of transforming growth factor-beta receptor I and 15-lipoxygenase in hypoxia-induced proliferation of pulmonary artery smooth muscle cells

Cited by 37 publications

References 26 publications

Vascular Endothelial Tight Junctions and Barrier Function Are Disrupted by 15(S)-Hydroxyeicosatetraenoic Acid Partly via Protein Kinase Cϵ-mediated Zona Occludens-1 Phosphorylation at Threonine 770/772

Vascular Endothelial Tight Junctions and Barrier Function Are Disrupted by 15(S)-Hydroxyeicosatetraenoic Acid Partly via Protein Kinase Cϵ-mediated Zona Occludens-1 Phosphorylation at Threonine 770/772

15-Lipoxygenase Promotes Chronic Hypoxia–Induced Pulmonary Artery Inflammation via Positive Interaction With Nuclear Factor-κB

EETs and CYP2J2 inhibit TNF-α-induced apoptosis in pulmonary artery endothelial cells and TGF-β1-induced migration in pulmonary artery smooth muscle cells

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