Role of TGF-β1 and MAP Kinases in the Antiproliferative Effect of Aspirin in Human Vascular Smooth Muscle Cells

Redondo, Santiago; Ruiz, Emilio Muñoz; Gordillo‐Moscoso, Antonio; Navarro‐Dorado, Jorge; Ramajo, Marta; Carnero, Manuel; Reguillo, Fernando del Rey; Rodrı́guez, Enrique; Tejerina, Teresa

doi:10.1371/journal.pone.0009800

Cited by 9 publications

(5 citation statements)

References 30 publications

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“…The results showed that the levels of plasma IL-35, IL-10 and TGF-β1 were dramatically decreased, whereas plasma IL-12 and IL-27 levels were significantly increased in patients with UAP and AMI compared with chest pain syndrome patients. Some studies found that aspirin could efficiently regulate the secretion of cytokines in vitro , whereas some showed contrary results [27]–[29]. In this study, we did not find a significant change in plasma levels of IL-35 and other cytokines after treatment with aspirin and clopidogrel, suggesting that a longer time is required to observe the effect of aspirin and clopidogrel on IL-35 production in vivo .…”

Section: Discussioncontrasting

confidence: 83%

Decreased Plasma IL-35 Levels Are Related to the Left Ventricular Ejection Fraction in Coronary Artery Diseases

Lin

Huang

et al. 2012

PLoS ONE

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BackgroundAccumulating evidence shows that the novel anti-inflammatory cytokine IL-35 can efficiently suppress effector T cell activity and alter the progression of inflammatory and autoimmune diseases. The two subunits of IL-35, EBI3 and p35, are strongly expressed in human advanced plaque, suggesting a potential role of IL-35 in atherosclerosis and coronary artery disease (CAD). However, the plasma levels of IL-35 in patients with CAD have yet to be investigated.MethodsPlasma IL-35, IL-10, TGF-β1, IL-12 and IL-27 levels were measured using an ELISA in 43 stable angina pectoris (SAP) patients, 62 unstable angina pectoris (UAP) patients, 56 acute myocardial infarction (AMI) patients and 47 chest pain syndrome patients as a control group.ResultsThe results showed that plasma IL-35 levels were significantly decreased in the SAP group (90.74±34.22 pg/ml), the UAP group (72.20±26.63 pg/ml), and the AMI group (50.21±24.69 pg/ml) compared with chest pain syndrome group (115.06±32.27 pg/ml). Similar results were also demonstrated with IL-10 and TGF-β1. Plasma IL-12 and IL-27 levels were significantly increased in the UAP group (349.72±85.22 pg/ml, 101.75±51.42 pg/ml, respectively) and the AMI group (318.05±86.82 pg/ml, 148.88±68.45 pg/ml, respectively) compared with chest pain syndrome group (138.68±34.37 pg/ml, 63.60±22.75 pg/ml, respectively) and the SAP group (153.84±53.86 pg/ml, 70.84±38.77 pg/ml, respectively). Furthermore, lower IL-35 levels were moderately positively correlated with left ventricular ejection fraction (LVEF) in CAD patients (R = 0.416, P<0.01), whereas higher IL-27 levels were weakly negatively correlated with LVEF in CAD patients(R = −0.205, P<0.01).ConclusionsThe results of the present study show that circulating IL-35 is a potentially novel biomarker for coronary artery disease. Regulating the expression of IL-35 also provides a new possible target for the treatment of atherosclerosis and CAD.

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Section: Discussioncontrasting

confidence: 83%

Decreased Plasma IL-35 Levels Are Related to the Left Ventricular Ejection Fraction in Coronary Artery Diseases

Lin

Huang

et al. 2012

PLoS ONE

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“…In order to examine if MIF plays a role in hypoxia-induced cell proliferation, we used bromodeoxyuridine (Brdu) incorporation assay[ 22 , 23 ] to study the proliferation of growth-arrested HUASMCs followed by co-treatment with specific MIF-siRNA (Santa Cruz Biotech, USA) and hypoxia (3% O 2 ) for 24 h. The specific MIF-siRNA could significantly inhibit MIF expression in HUVSMCs under both normoxia and hypoxia conditions (Figure 5 ).…”

Section: Resultsmentioning

confidence: 99%

“…The effect of hypoxia on cell proliferation was determined by the bromodeoxyuridine (BrdU) incorporation assay, as described previously [ 22 , 23 ]. Briefly, HUASMC cells were subcultured in 96-well plates and incubated with serum-free medium for 24 h in order to synchronize the cells in G 0 /G 1 phase.…”

Section: Methodsmentioning

confidence: 99%

Hypoxia stimulates the expression of macrophage migration inhibitory factor in human vascular smooth muscle cells via HIF-1α dependent pathway

Luo

Yang

et al. 2010

BMC Cell Biol

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BackgroundHypoxia plays an important role in vascular remodeling and directly affects vascular smooth muscle cells (VSMC) functions. Macrophage migration inhibitory factor (MIF) is a well known proinflammatory factor, and recent evidence suggests an important role of MIF in the progression of atherosclerosis and restenosis. However, the potential link between hypoxia and MIF in VSMC has not been investigated. The current study was designed to test whether hypoxia could regulate MIF expression in human VSMC. The effect of modulating MIF expression on hypoxia-induced VSMC proliferation and migration was also investigated at the same time.ResultsExpression of MIF mRNA and protein was up-regulated as early as 2 hours in cultured human VSMCs after exposed to moderate hypoxia condition (3% O2). The up-regulation of MIF expression appears to be dependent on hypoxia-inducible transcription factor-1α(HIF-1α) since knockdown of HIF-1α inhibits the hypoxia induction of MIF gene and protein expression. The hypoxia induced expression of MIF was attenuated by antioxidant treatment as well as by inhibition of extracellular signal-regulated kinase (ERK). Under moderate hypoxia conditions (3% O2), both cell proliferation and cell migration were increased in VSMC cells. Blocking the MIF by specific small interference RNA to MIF (MIF-shRNA) resulted in the suppression of proliferation and migration of VSMCs.ConclusionOur results demonstrated that in VSMCs, hypoxia increased MIF gene expression and protein production. The hypoxia-induced HIF-1α activation, reactive oxygen species (ROS) generation and ERK activation might be involved in this response. Both MIF and HIF-1α mediated the hypoxia response of vascular smooth muscle cells, including cell migration and proliferation.

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“…[ 27 ] TGF-β1 was found to work through the p38 MAPK signal pathway but not JNK. [ 28 29 30 31 32 33 34 35 ] Thus, we postulated that p38, but not JNK, was involved in the LPS-induced acute pulmonary fibroproliferation and JNK inhibitor had no obvious effect on pulmonary fibrosis in ARDS.…”

Section: Discussionmentioning

confidence: 97%

Inhibition of c-Jun N-terminal Kinase Signaling Pathway Alleviates Lipopolysaccharide-induced Acute Respiratory Distress Syndrome in Rats

Lai

Qiu

Chen

et al. 2016

Chinese Medical Journal

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Background:An acute respiratory distress syndrome (ARDS) is still one of the major challenges in critically ill patients. This study aimed to investigate the effect of inhibiting c-Jun N-terminal kinase (JNK) on ARDS in a lipopolysaccharide (LPS)-induced ARDS rat model.Methods:Thirty-six rats were randomized into three groups: control, LPS, and LPS + JNK inhibitor. Rats were sacrificed 8 h after LPS treatment. The lung edema was observed by measuring the wet-to-dry weight (W/D) ratio of the lung. The severity of pulmonary inflammation was observed by measuring myeloperoxidase (MPO) activity of lung tissue. Moreover, the neutrophils in bronchoalveolar lavage fluid (BALF) were counted to observe the airway inflammation. In addition, lung collagen accumulation was quantified by Sircol Collagen Assay. At the same time, the pulmonary histologic examination was performed, and lung injury score was achieved in all three groups.Results:MPO activity in lung tissue was found increased in rats treated with LPS comparing with that in control (1.26 ± 0.15 U in LPS vs. 0.77 ± 0.27 U in control, P < 0.05). Inhibiting JNK attenuated LPS-induced MPO activity upregulation (0.52 ± 0.12 U in LPS + JNK inhibitor vs. 1.26 ± 0.15 U in LPS, P < 0.05). Neutrophils in BALF were also found to be increased with LPS treatment, and inhibiting JNK attenuated LPS-induced neutrophils increase in BALF (255.0 ± 164.4 in LPS vs. 53 (44.5-103) in control vs. 127.0 ± 44.3 in LPS + JNK inhibitor, P < 0.05). At the same time, the lung injury score showed a reduction in LPS + JNK inhibitor group comparing with that in LPS group (13.42 ± 4.82 vs. 7.00 ± 1.83, P = 0.001). However, the lung W/D ratio and the collagen in BALF did not show any differences between LPS and LPS + JNK inhibitor group.Conclusions:Inhibiting JNK alleviated LPS-induced acute lung inflammation and had no effects on pulmonary edema and fibrosis. JNK inhibitor might be a potential therapeutic medication in ARDS, in the context of reducing lung inflammatory.

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Role of TGF-β1 and MAP Kinases in the Antiproliferative Effect of Aspirin in Human Vascular Smooth Muscle Cells

Cited by 9 publications

References 30 publications

Decreased Plasma IL-35 Levels Are Related to the Left Ventricular Ejection Fraction in Coronary Artery Diseases

Decreased Plasma IL-35 Levels Are Related to the Left Ventricular Ejection Fraction in Coronary Artery Diseases

Hypoxia stimulates the expression of macrophage migration inhibitory factor in human vascular smooth muscle cells via HIF-1α dependent pathway

Inhibition of c-Jun N-terminal Kinase Signaling Pathway Alleviates Lipopolysaccharide-induced Acute Respiratory Distress Syndrome in Rats

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