Cyclooxygenase-2-Linked Attenuation of Hypoxia-Induced Pulmonary Hypertension and Intravascular Thrombosis

Abstract

Exogenous prostacyclin is effective in reducing pulmonary vascular resistance in some forms of human pulmonary hypertension (PH). To explore whether endogenous prostaglandins played a similar role in pulmonary hypertension, we examined the effect of deleting cyclooxygenase (COX)-gene isoforms in a chronic hypoxia model of PH. Pulmonary hypertension, examined by direct measurement of right ventricular end systolic pressure (RVESP), right ventricular hypertrophy (n ϭ 8), and hematocrit (n ϭ 3), was induced by 3 weeks of hypobarichypoxia in wild-type and COX-knockout (KO) mice. RVESP was increased in wild-type hypoxic mice compared with normoxic controls (24.4 Ϯ 1.4 versus 13.8 Ϯ 1.9 mm Hg; n ϭ 8; p Ͻ 0.05). COX-2 KO mice showed a greater increase in RVESP following hypoxia (36.8 Ϯ 2.7 mm Hg; p Ͻ 0.05). Urinary thromboxane (TX)B 2 excretion increased following hypoxia (44.6 Ϯ 11.1 versus 14.7 Ϯ 1.8 ng/ml; n ϭ 6; p Ͻ 0.05), an effect that was exacerbated by COX-2 gene disruption (54.5 Ϯ 10.8 ng/ml; n ϭ 6). In contrast, the increase in 6-keto-prostacyclin 1␣ excretion following hypoxia was reduced by COX-2 gene disruption (29 Ϯ 3 versus 52 Ϯ 4.6 ng/ml; p Ͻ 0.01). Tail cut bleed times were lower following hypoxia, and there was evidence of intravascular thrombosis in lung vessels that was exacerbated by disruption of COX-2 and reduced by deletion of COX-1. The TXA 2 / endoperoxide receptor antagonist ifetroban (50 mg/kg/day) offset the effect of deleting the COX-2 gene, attenuating the hypoxia-induced rise in RVESP and intravascular thrombosis. COX-2 gene deletion exacerbates pulmonary hypertension, enhances sensitivity to TXA 2 , and induces intravascular thrombosis in response to hypoxia. The data provide evidence that endogenous prostaglandins modulate the pulmonary response to hypoxia.Pulmonary hypertension (PH) is characterized by an elevation in pulmonary vascular tone and a striking degree of pulmonary vascular remodeling. As a consequence, there is increased pulmonary vascular resistance and right ventricular hypertrophy that ultimately leads to right ventricular failure and death (Blumberg et al., 2002). Prostaglandins have been implicated in the pathogenesis of at least some forms of PH (Christman et al., 1992). These bioactive products are generated by the enzyme cyclooxygenase (COX

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

“…COX-2 expression is increased in lung tissues from PAH patients and in PAs from hypoxia-induced PAH mouse models (4,5). As such, we also observed the substantial induction of all PG products, including PGE 2 (Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI77656DS1) in lungs in response to chronic hypoxia.…”

“…COX-1 is ubiquitously expressed in lung tissue, while COX-2 can be induced in the smooth muscle layer of pulmonary blood vessels by chronic hypoxia (4,5). Disruption or knockdown of COX-2 exacerbates hypoxia-and monocrotaline-induced (MCT-induced) pulmonary hypertension and enhances the contractility of VSMCs (6,7).…”

Type 1 Diabetes-Induced Hyper-Responsiveness to 5-Hydroxytryptamine in Rat Pulmonary Arteries via Oxidative Stress and Induction of Cyclooxygenase-2

“…Thus, inhibition of COX-2 by celecoxib exhibited beneficial effects against the development of monocrotaline-induced PAH (Rakotoniaina et al, 2008). In contrast, hypoxia-induced PAH was exacerbated by the celecoxib derivative 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide (SC236) (Pidgeon et al, 2004) and in COX-2 knockout animals (Cathcart et al, 2008;Fredenburgh et al, 2008). Herein, we found that acute inhibition of COX-2 can prevent the hypercontractile response to 5-HT in diabetic rats as previously found in PAH induced by intermittent hypoxia (Thomas and Wanstall, 2003) or high pulmonary blood flow (Sato et al, 2000).…”

The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer

“…It was demonstrated that COX-2 dependant PGI 2 formation limits the pulmonary hypertensive response to hypoxia in-vivo, partly through attenuation of TXA 2 -dependant platelet activation and deposition. These observations were later confirmed in a COX-gene disrupted mouse model of pulmonary hypertension [28]. This model Immunohistochemical examination of expression profiles of the COX enzymes and downstream enzymes of COX metabolism in lung cancer showed that COX-2 and TXS expression was abundant in lung cancer, but that PGIS expression was absent [30].…”