article · Circulation Research
Inflammatory cytokines are known to contribute to pulmonary hypertension, a condition often treated with prostacyclin analogues that dilate vessels by raising cyclic AMP levels. Exposure of human pulmonary artery smooth muscle cells to bradykinin, interleukin-1beta, and transforming growth factor-beta1 significantly reduces cyclic AMP accumulation in response to prostacyclin analogues such as iloprost and carbaprostacyclin. This reduction occurs because these inflammatory mediators trigger the production of cyclooxygenase-2 and the release of prostaglandin E2. Consequently, adenylyl cyclase isoforms 1, 2, and 4 are downregulated. Blocking cyclooxygenase-2 with a selective inhibitor reverses this suppression of cyclic AMP production. These findings reveal a biological pathway through which inflammatory molecules produced in pulmonary hypertension could diminish the effectiveness of prostacyclin analogue therapies by altering adenylyl cyclase activity.
Prostacyclin analogues are critical therapies for relaxing blood vessels in patients with pulmonary hypertension. Understanding how inflammatory molecules blunt cellular responsiveness to these medicines explains why treatments may lose effectiveness. Identifying the involvement of cyclooxygenase-2 clarifies the molecular connections between inflammation and drug resistance, helping researchers explore strategies to preserve or restore therapeutic responses.
This early-stage cellular research reveals how inflammatory signalling interferes with standard pulmonary hypertension treatments like iloprost. The findings could inform future drug discovery programmes seeking combination therapies, particularly evaluating whether selective cyclooxygenase-2 inhibitors can protect prostacyclin responsiveness. As laboratory research on cultured human cells, practical clinical applications remain distant and will require extensive preclinical validation.
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Increased levels of inflammatory cytokines contribute to the pathophysiology of pulmonary hypertension. Prostacyclin (PGI2) analogues, which relax pulmonary vessels mainly through cAMP elevation, have a major therapeutic role. In this study, we show that prolonged incubation with bradykinin (BK), interleukin-1beta (IL-1beta), and transforming growth factor-beta1 (TGF-beta1) markedly impairs cAMP accumulation in human pulmonary artery smooth muscle cells in response to short-term incubation with prostaglandin E2 (PGE2) and the PGI2 analogues iloprost and carbaprostacyclin. A similar reduction in cAMP accumulation in response to a direct adenylyl cyclase activator, forskolin, suggested that the effect was attributable to downregulation of adenylyl cyclase. Reverse transcriptase-polymerase chain reaction studies showed downregulation of adenylyl cyclase isoforms 1, 2, and 4. The effect of IL-1beta, BK, and TGF-beta1 on cAMP levels was abrogated by the selective COX-2 inhibitor NS398. Furthermore, it was mimicked by prolonged incubation with the COX-2 product PGE2 and PGI2 analogues or the COX substrate arachidonic acid, suggesting that it was mediated by endogenous prostanoids produced by COX-2. Consistent with this, IL-1beta, BK, and TGF-beta1 all induced COX-2 and PGE2 release. These results show that BK, IL-1beta, and TGF-beta1 downregulate adenylyl cyclase in human pulmonary artery smooth muscle cells via COX-2 induction and prostanoid release. This suggests a novel mechanism whereby mediators and cytokines produced in pulmonary hypertension may impair the therapeutic effects of prostacyclin analogues such as iloprost and carbaprostacyclin.
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DOI: 10.1161/01.res.0000111801.48626.f4
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