Estrogen Protects the Heart From Ischemia-Reperfusion Injury via COX-2-Derived PGI2

Booth, Erin A.; Flint, RaShonda Renee; Lucas, Kathryn Louise; Knittel, Andrea K.; Lucchesi, Benedict R.

doi:10.1097/fjc.0b013e3181824d59

Cited by 32 publications

(22 citation statements)

References 37 publications

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“…For example, in the cardiovascular system, COX-2 usually exerts beneficial effects. As previously demonstrated, the cardioprotective effects of estrogen, zileuton and atorvastatin are mediated by COX-2 (27,29,30). In accordance with a previous study (2), our data demonstrated that exposure to CoCl 2 markedly reduced COX-2 expression in the HPASMCs.…”

Section: Discussionsupporting

confidence: 81%

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H2S inhibition of chemical hypoxia-induced proliferation of HPASMCs is mediated by the upregulation of COX-2/PGI2

Liu

Cai

et al. 2013

International Journal of Molecular Medicine

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Abstract. The hypoxia-induced proliferation of pulmonary artery smooth muscle cells (PASMCs) is the main cause of pulmonary arterial hypertension (PAH), in which oxidative stress, cyclooxygenase (COX)-2 and hydrogen sulfide (H 2 S) all play an important role. In the present study, we aimed to examine the effects of H 2 S on the hypoxia-induced proliferation of human PASMCs (HPASMCs) and to elucidate the underlying mechanisms. The HPASMCs were treated with cobalt chloride (CoCl 2 ), a hypoxia-mimicking agent, to establish a cellular model of hypoxic PAH. Prior to treatment with CoCl 2 , the cells were pre-conditioned with sodium hydrosulfide (NaHS), a donor of H 2 S. Cell proliferation, reactive oxygen species (ROS) production, COX-2 expression, prostacyclin (also known as prostaglandin I2 or PGI 2 ) secretion and H 2 S levels were detected in the cells. The exposure of the HPASMCs to CoCl 2 markedly increased cell proliferation, accompanied by a decrease in COX-2 expression, PGI 2 secretion and H 2 S levels; however, the levels of ROS were not altered. Although the exogenous ROS donor, H 2 O 2 , triggered similar degrees of proliferation to CoCl 2 , the ROS scavenger, N-acetyl-L-cysteine (NAC), markedly abolished the H 2 O 2 -induced cell proliferation, as opposed to the CoCl 2 -induced proliferation. The CoCl 2 -induced proliferation of HPASMCs was suppressed by exogenously applied PGI 2 . The addition of H 2 S (NaHS) attenuated the CoCl 2 -induced cell proliferation through the increase in the intercellular content of H 2 S. Importantly, the exposure of the cells to H 2 S suppressed the CoCl 2 -induced downregulation in COX-2 expression and PGI 2 secretion from the HPASMCs. In conclusion, the results from the current study suggest that H 2 S inhibits hypoxia-induced cell proliferation through the upregulation of COX-2/PGI 2 , as opposed to ROS.

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Section: Discussionsupporting

confidence: 81%

“…COX-2 is a multifunctional protein, whose roles are complex and ambivalent in different models, mediating either neuronal toxicity or cardiac protection (27,28). For example, in the cardiovascular system, COX-2 usually exerts beneficial effects.…”

Section: Discussionmentioning

confidence: 99%

H2S inhibition of chemical hypoxia-induced proliferation of HPASMCs is mediated by the upregulation of COX-2/PGI2

Liu

Cai

et al. 2013

International Journal of Molecular Medicine

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“…The roles of COX-2 overexpression are complicated and ambivalent in different models, mediating either cytotoxicity or cytoprotection (Booth et al, 2008;Carnieto et al, 2009;Ito et al, 2003;Kwak et al, 2010;Oh et al, 2010;Tu et al, 2009;Yun et al, 2009). Some studies indicated that inhibition of COX-2 activation attenuated ischemic neuronal injury, characterized by a decrease in cerebral infarction and CA1 hippocampal neuron death (Dore et al, 2003;Nakayama et al, 1998), while other reports showed that during cardiotoxicity induced by ischemia-reperfusion (I/R), up-regulation of COX-2 expression obviously possessed protective effects (Booth et al, 2008;Kwak et al, 2010). However, the role of COX-2 in hypoxic injury of skin remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress Mediates Chemical Hypoxia-Induced Injury and Inflammation by Activating NF-κb-COX-2 Pathway in HaCaT Cells

Liu

Ling

Mei-fen

et al. 2011

Molecules and Cells

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Hypoxia of skin is an important physiopathological process in many diseases, such as pressure ulcer, diabetic ulcer, and varicose ulcer. Although cellular injury and inflammation have been involved in hypoxia-induced dermatic injury, the underlying mechanisms remain largely unknown. This study was conducted to investigate the effects of cobalt chloride (CoCl 2 ), a hypoxia-mimicking agent, on human skin keratinocytes (HaCaT cells) and to explore the possible molecular mechanisms. Exposure of HaCaT cells to CoCl 2 reduced cell viability and caused overproduction of reactive oxygen species (ROS) and oversecretion of interleukin-6 (IL-6) and interleukin-8 (IL-8). Importantly, CoCl 2 exposure elicited overexpression of cyclooxygenase-2 (COX-2) and phosphorylation of nuclear factor-kappa B (NF-κB) p65 subunit. Inhibition of COX-2 by NS-398, a selective inhibitor of COX-2, significantly repressed the cytotoxicity, as well as secretion of IL-6 and IL-8 induced by CoCl 2 . Inhibition of NF-κB by PDTC (a selective inhibitor of NF-κB) or genetic silencing of p65 by RNAi (Si-p65), attenuated not only the cytotoxicity and secretion of IL-6 and IL-8, but also overexpression of COX-2 in CoCl 2 -treated HaCaT cells. Neutralizing anti-IL-6 or anti-IL-8 antibody statistically alleviated CoCl 2 -induced cytotoxicity in HaCaT cells. N-acetyl-L-cysteine (NAC), a well characterized ROS scavenger, obviously suppressed CoCl 2 -induced cytotoxicity in HaCaT cells, as well as secretion of IL-6 and IL-8. Additionally, NAC also repressed overexpression of COX-2 and phosphorylation of NF-B κ p65 subunit induced by CoCl 2 in HaCaT cells. In conclusion, our results demonstrated that oxidative stress mediates chemical hypoxia-induced injury and inflammatory response through activation of NF-κB-COX-2 pathway in HaCaT cells.

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“…Constitutive expression of COX-2 in cardiomyocytes also represents a protective mechanism against reperfusion injury [150]. Protective effects of oestrogen in ischaemia ⁄ reperfusion have been suggested to be mediated by activation of COX-2 and subsequently prostaglandin I-2 [151]. Cardioprotective effects of a 5-lipoxygenase inhibitor have been shown to be mediated by COX-2 because of protein kinase C activation [152].…”

Section: Myocardial Perfusion Defects In Bartter and Gitelman Syndrommentioning

confidence: 98%

Research update for articles published in EJCI in 2008

Anderwald

Ankersmit²,

Badaoui³

et al. 2010

Eur J Clin Investigation

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Estrogen Protects the Heart From Ischemia-Reperfusion Injury via COX-2-Derived PGI2

Cited by 32 publications

References 37 publications

H2S inhibition of chemical hypoxia-induced proliferation of HPASMCs is mediated by the upregulation of COX-2/PGI2

H2S inhibition of chemical hypoxia-induced proliferation of HPASMCs is mediated by the upregulation of COX-2/PGI2

Oxidative Stress Mediates Chemical Hypoxia-Induced Injury and Inflammation by Activating NF-κb-COX-2 Pathway in HaCaT Cells

Research update for articles published in EJCI in 2008

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