EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling

Lü, Ankang; Zuo, Caojian; He, Yuefeng; Chen, Guilin; Piao, Lingjuan; Zhang, Jian; Xiao, Bing; Shen, Yujun; Tang, Juan; Kong, Deping; Alberti, Sara; Chen, Di; Zuo, Shenkai; Zhang, Qianqian; Yan, Shuai; Fei, Xiaochun; Yuan, Fei; Zhou, Bin; Duan, Sheng‐Zhong; Yu, Yu; Lazarus, Michael; Su, Yunchao; Breyer, Richard M.; Funk, Colin D.; Yu, Ying

doi:10.1172/jci77656

Cited by 73 publications

(82 citation statements)

References 73 publications

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“…Given that EP3 inhibition or knockdown restored TCDD‐caused‐p38 MAPK activation and suppressed Bcl‐2 expression, EP3‐mediated activation of the p38MAPK/Bcl‐2 pathway contributes to apoptosis increased by TCDD in HUVECs. Rho activates p38 MAPK 36, 37, 38 and the EP3 receptor couples small G protein and activates RhoA 24, 28. Indeed, we demonstrated that TCDD exposure increased p38 MAPK phosphorylation by activating EP3/Rho signalling in HUVECs.…”

Section: Discussionmentioning

confidence: 58%

“…As the EP3 receptor is linked to the small GTP‐binding protein Rho 24, 28, and Rho activates the p38 MAPK pathway 36, 37, 38, we investigated whether Rho mediates p38 activation in TCDD‐elicited apoptosis in HUVECs. Non‐radioactive Rho pull‐down assay showed that RhoA activity was minimal in unstimulated HUVECs, but was greatly increased following TCDD treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

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2, 3, 7, 8‐Tetrachlorodibenzo‐p‐dioxin promotes endothelial cell apoptosis through activation of EP3/p38MAPK/Bcl‐2 pathway

Liu

Guo

et al. 2017

J Cellular Molecular Medi

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Endothelial injury or dysfunction is an early event in the pathogenesis of atherosclerosis. Epidemiological and animal studies have shown that 2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin (TCDD) exposure increases morbidity and mortality from chronic cardiovascular diseases, including atherosclerosis. However, whether or how TCDD exposure causes endothelial injury or dysfunction remains largely unknown. Cultured human umbilical vein endothelial cells (HUVECs) were exposed to different doses of TCDD, and cell apoptosis was examined. We found that TCDD treatment increased caspase 3 activity and apoptosis in HUVECs in a dose‐dependent manner,at doses from 10 to 40 nM. TCDD increased cyclooxygenase enzymes (COX)‐2 expression and its downstream prostaglandin (PG) production (mainly PGE2 and 6‐keto‐PGF1α) in HUVECs. Interestingly, inhibition of COX‐2, but not COX‐1, markedly attenuated TCDD‐triggered apoptosis in HUVECs. Pharmacological inhibition or gene silencing of the PGE2 receptor subtype 3 (EP3) suppressed the augmented apoptosis in TCDD‐treated HUVECs. Activation of the EP3 receptor enhanced p38 MAPK phosphorylation and decreased Bcl‐2 expression following TCDD treatment. Both p38 MAPK suppression and Bcl‐2 overexpression attenuated the apoptosis in TCDD‐treated HUVECs. TCDD increased EP3‐dependent Rho activity and subsequently promoted p38MAPK/Bcl‐2 pathway‐mediated apoptosis in HUVECs. In addition, TCDD promoted apoptosis in vascular endothelium and delayed re‐endothelialization after femoral artery injury in wild‐type (WT) mice, but not in EP3−/− mice. In summary, TCDD promotes endothelial apoptosis through the COX‐2/PGE2/EP3/p38MAPK/Bcl‐2 pathway. Given the cardiovascular hazard of a COX‐2 inhibitor, our findings indicate that the EP3 receptor and its downstream pathways may be potential targets for prevention of TCDD‐associated cardiovascular diseases.

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Section: Discussionmentioning

confidence: 58%

Section: Resultsmentioning

confidence: 99%

2, 3, 7, 8‐Tetrachlorodibenzo‐p‐dioxin promotes endothelial cell apoptosis through activation of EP3/p38MAPK/Bcl‐2 pathway

Liu

Guo

et al. 2017

J Cellular Molecular Medi

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“…Morphological evidence was identified in our study to support the hypothesis that PAs vessel remodeling induced by hypoxia in vivo is mediated by TGFβ1. TGFβ1 has been implicated as a primary contributor to the pathogenesis of PAH (Gilbane, Derrett-Smith, 2015, Lu, Zuo, 2015, Ostriker, Horita, 2014. In vitro studies using PASMCs implicated hypoxia and TGFβ1-mediated downregulation of PTEN expression as a key mechanism of SMC proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…TGFβ1, a multifunctional cytokine, regulates cell proliferation, growth, differentiation and cell movement through receptors and various intracellular signaling pathways (Kajdaniuk et al , 2013). There is a growing body of evidence that suggests that abnormalities of TGFβ1 signalling pathway are linked to the pathogenesis of PAH (Gilbane et al , 2015, Lu et al , 2015, Ostriker et al , 2014, and that TGFβ1 protectes against apoptosis of pulmonary artery endothelial cell (PAEC) (Lu, 2008, Mauro et al , 2001.…”

mentioning

confidence: 99%

Transforming growth factor-beta1 upregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PTEN/AKT pathways

Liu

Cao

Sun

et al. 2016

The International Journal of Biochemistry & Cell Biology

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“…Cell supernatants or peritoneal exudates (500 ml) were used for PG extraction after protein quantification, as previously reported (Lu et al, 2015). An internal standard (2 ml) was added to the sample in 40 ml of citric acid (1 M) and 5 ml of 10% butylated hydroxytoluene, and the sample was then vigorously shaken with 1 ml of solvent (normal hexane:ethyl acetate, 1:1) for 1 minute.…”

Section: Neutrophilsmentioning

confidence: 99%

Niacin Promotes Cardiac Healing after Myocardial Infarction through Activation of the Myeloid Prostaglandin D₂ Receptor Subtype 1

Kong

Shen

et al. 2017

J Pharmacol Exp Ther

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Niacin is a well established drug used to lower cholesterol and prevent cardiovascular disease events. However, niacin also causes cutaneous flushing side effects due to release of the proresolution mediator prostaglandin D 2 (PGD 2 ). Recent randomized clinical trials have demonstrated that addition of niacin with laropiprant [a PGD 2 receptor subtype 1 (DP1) blocker] to statin-based therapies does not significantly decrease the risk of cardiovascular disease events, but increases the risk of serious adverse events. Here, we tested whether, and how, niacin beneficial effects on myocardial ischemia require the activation of the PGD 2 /DP1 axis. Myocardial infarction (MI) was reproduced by ligation of the left anterior descending branch of the coronary artery in mice. We found that niacin increased PGD 2 release in macrophages and shifted macrophages to M2 polarization both in vitro and in vivo by activation of DP1 and accelerated inflammation resolution in zymosan-induced peritonitis in mice. Moreover, niacin treatment facilitated wound healing and improved cardiac function after MI through DP1-mediated M2 bias and timely resolution of inflammation in infarcted hearts. In addition, we found that niacin intake also stimulated M2 polarization of peripheral monocytes in humans. Collectively, niacin promoted cardiac functional recovery after ischemic myocardial infarction through DP1-mediated M2 polarization and timely resolution of inflammation in hearts. These results indicated that DP1 inhibition may attenuate the cardiovascular benefits of niacin.

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EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling

Cited by 73 publications

References 73 publications

2, 3, 7, 8‐Tetrachlorodibenzo‐p‐dioxin promotes endothelial cell apoptosis through activation of EP3/p38MAPK/Bcl‐2 pathway

2, 3, 7, 8‐Tetrachlorodibenzo‐p‐dioxin promotes endothelial cell apoptosis through activation of EP3/p38MAPK/Bcl‐2 pathway

Transforming growth factor-beta1 upregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PTEN/AKT pathways

Niacin Promotes Cardiac Healing after Myocardial Infarction through Activation of the Myeloid Prostaglandin D₂ Receptor Subtype 1

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EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling

Cited by 73 publications

References 73 publications

2, 3, 7, 8‐Tetrachlorodibenzo‐p‐dioxin promotes endothelial cell apoptosis through activation of EP3/p38MAPK/Bcl‐2 pathway

2, 3, 7, 8‐Tetrachlorodibenzo‐p‐dioxin promotes endothelial cell apoptosis through activation of EP3/p38MAPK/Bcl‐2 pathway

Transforming growth factor-beta1 upregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PTEN/AKT pathways

Niacin Promotes Cardiac Healing after Myocardial Infarction through Activation of the Myeloid Prostaglandin D2 Receptor Subtype 1

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Niacin Promotes Cardiac Healing after Myocardial Infarction through Activation of the Myeloid Prostaglandin D₂ Receptor Subtype 1