Absence of Cyclooxygenase-2 Exacerbates Hypoxia-Induced Pulmonary Hypertension and Enhances Contractility of Vascular Smooth Muscle Cells

Fredenburgh, Laura E.; Liang, Olin D.; Macias, Alvaro A.; Polte, Thomas R.; Liu, Xiaoli; Riascos, Dario F.; Chung, Sung Min; Schissel, Scott L.; Ingber, Donald E.; Mitsialis, S. Alex; Kourembanas, Stella; Perrella, Mark A.

doi:10.1161/circulationaha.107.716241

Cited by 77 publications

(74 citation statements)

References 41 publications

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“…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. Our data further indicated that PGI 2 , a product of COX-2 from cells was also markedly reduced.…”

Section: Discussionsupporting

confidence: 93%

“…The hallmark of PAH is the development of gradually increased pulmonary vascular resistance, which eventually enhances the afterload of the right ventricle and leads to right heart failure (1). The etiopathogenesis of PAH is commonly associated with chronic hypoxemia in disorders, such as chronic obstructive pulmonary disease and interstitial lung disease (2). Increasing evidence indicates that apart from vasoconstriction, smooth muscle cell proliferation and hypertrophy, usually leading to pulmonary vascular remodeling and increased resistance, play a crucial role in the development of PAH (3).…”

Section: Introductionmentioning

confidence: 99%

“…Of note, prostacyclin (also known as prostaglandin I2 or PGI 2 ), an effective but expensive clinical drug, has been used for the treatment of PAH via vasodilatation (10). The endogenous formation of PGI 2 is mainly attributed to normal cyclooxygenase-2 (COX-2) expression; however, COX-2 expression is reportedly downregulated in hypoxia-induced PAH (2).…”

Section: Introductionmentioning

confidence: 99%

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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: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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 effect of untransformed PGH 2 itself would be blocked by use of COX inhibitors and/or receptor antagonists; however, these approaches might be somewhat non-specific irrespective of disease status, leading to undesirable effects including potential cardiovascular risks. In this regard, it has been demonstrated that absence or inhibition of COX-2 exacerbates hypoxia-induced PAH and enhances contractility of VSMCs (27). Our present study suggests an important role of sPLA 2 in the stretch-induced rhythmic contraction of pulmonary arteries of MCT-PHR.…”

Section: +supporting

confidence: 65%

Role of Secretory Phospholipase A2 in Rhythmic Contraction of Pulmonary Arteries of Rats With Monocrotaline-Induced Pulmonary Arterial Hypertension

et al. 2012

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Abstract. Excessive stretching of the vascular wall in accordance with pulmonary arterial hypertension (PAH) induces a variety of pathogenic cellular events in the pulmonary arteries. We previously reported that indoxam, a selective inhibitor for secretory phospholipase A 2 (sPLA 2 ), blocked the stretch-induced contraction of rabbit pulmonary arteries by inhibition of untransformed prostaglandin H 2 (PGH 2 ) production. The present study was undertaken to investigate involvement of sPLA 2 and untransformed PGH 2 in the enhanced contractility of pulmonary arteries of experimental PAH in rats. Among all the known isoforms of sPLA 2 , sPLA 2 -X transcript was most significantly augmented in the pulmonary arteries of rats with monocrotaline-induced pulmonary hypertension (MCT-PHR). The pulmonary arteries of MCT-PHR frequently showed two types of spontaneous contraction in response to stretch; 27% showed rhythmic contraction, which was sensitive to indoxam and SC-560 (selective COX-1 inhibitor), but less sensitive to NS-398 (selective COX-2 inhibitor); and 47% showed sustained incremental tension (tonic contraction), which was insensitive to indoxam and SC-560, but sensitive to NS-398 and was attenuated to 45% of the control. Only the rhythmically contracting pulmonary arteries of MCT-PHR produced a substantial amount of untransformed PGH 2 , which was abolished by indoxam. These results suggest that sPLA 2 -mediated PGH 2 synthesis plays an important role in the rhythmic contraction of pulmonary arteries of MCT-PHR.

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“…For quantitative analyses, 30 vessels from each rat were counted and the average was calculated. At 6400 magnification, 80 small pulmonary vessels of each animal ranging from 10 to 50 mm in external diameter were evaluated for muscularisation [12]. of 6400, in a blind manner [13].…”

Section: Histological Analyses and Morphometrymentioning

confidence: 99%

Oestradiol ameliorates monocrotaline pulmonary hypertensionviaNO, prostacyclin and endothelin-1 pathways

Yuan

Gao³

et al. 2012

Eur Respir J

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Pulmonary hypertension continues to be a serious clinical problem with high mortality. As oestrogen is a potential vasodilator of the pulmonary circulation, this study examined the mechanisms by which 17b-oestradiol improves monocrotaline (MCT)-induced pulmonary hypertension.Female Sprague-Dawley rats underwent bilateral ovariectomy or sham operations. The rats received MCT (50 mg?kg -1 ) and were treated with 17b-oestradiol (1 mg?kg -1 per day) for either 5 weeks or only from week 4 to week 5. Plasma 17b-oestradiol concentrations were decreased in sham-operated, MCT-treated rats when compared with sham-operated rats (17.7¡4.7 versus 50.3¡15.4 pg?mL -1 ; p50.029). The 17b-oestradiol anabolic enzyme cytochrome P450 (CYP)-19 was decreased by MCT treatment, while the catabolic enzymes CYP-1A1 and -1B1 were increased. Ovariectomised and MCT-treated rats had more severe pulmonary hypertension. 17b-oestradiol suppressed pulmonary arterial smooth muscle cell proliferation and macrophage infiltration, and enhanced apoptosis by increasing nitric oxide (NO) and prostacyclin (prostaglandin (PG)I 2 ) levels and reducing endothelin (ET)-1 levels. Phosphoinositide-3-kinase (PI3K) and Akt phosphorylations were markedly increased, but were inhibited by 17b-oestradiol treatment in rats with pulmonary hypertension. Oestrogen deficiency may aggravate development of pulmonary hypertension. 17b-oestradiol improved pulmonary hypertension via activation of the PI3K/Akt pathway to regulate NO, PGI 2 and ET-1 expression.

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Absence of Cyclooxygenase-2 Exacerbates Hypoxia-Induced Pulmonary Hypertension and Enhances Contractility of Vascular Smooth Muscle Cells

Cited by 77 publications

References 41 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

Role of Secretory Phospholipase A2 in Rhythmic Contraction of Pulmonary Arteries of Rats With Monocrotaline-Induced Pulmonary Arterial Hypertension

Oestradiol ameliorates monocrotaline pulmonary hypertensionviaNO, prostacyclin and endothelin-1 pathways

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