article · Journal of Biological Chemistry
In human pulmonary artery smooth muscle cells, the inflammatory mediator bradykinin triggers the induction of cyclooxygenase-2 through a specific transcriptional pathway. Genetic reporter experiments demonstrate that this activation relies on the cyclic AMP response element binding site within the cyclooxygenase-2 promoter, rather than other common regulatory elements. Bradykinin promotes the release of arachidonic acid via cytosolic phospholipase A2, leading to rapid synthesis of prostaglandin E2 and subsequent increases in cyclic AMP. This autocrine loop drives promoter activity, a process that can be blocked using indomethacin. Furthermore, the effects of bradykinin are replicated by applying exogenous prostaglandin E2 as well as specific agonists targeting the E-prostanoid 2 and E-prostanoid 4 receptors. These findings identify an autocrine feedback mechanism that regulates inflammatory gene expression in vascular smooth muscle cells.
Bradykinin is a critical driver of vascular and inflammatory diseases. Uncovering the exact cellular signals that control cyclooxygenase-2 induction helps clarify how vascular tissue sustains inflammatory responses. By mapping the autocrine role of prostaglandin E2 and specific prostanoid receptors, these insights provide foundational knowledge on the regulatory pathways active in human pulmonary arterial cells during inflammation.
This is early-stage fundamental research clarifying cellular signalling mechanisms in cell cultures. While the abstract does not describe a commercial product or clinical trial, identifying the involvement of E-prostanoid 2 and 4 receptors and prostaglandin E2 points to potential therapeutic targets. Drug discovery researchers investigating inflammatory vascular conditions could explore these specific receptor pathways, though significant preclinical validation remains necessary before therapeutic applications can emerge.
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Bradykinin (BK) is an important mediator in several inflammatory and vascular diseases that acts in part via induction of cyclooxygenase-2 (COX-2). The mechanisms involved in BK-mediated COX-2 induction are unclear. Here we characterized the transcriptional mechanisms involved in human pulmonary artery smooth muscle cells. BK stimulated the activity of a transiently transfected 966-bp (-917 to + 49) COX-2 promoter luciferase reporter construct. There was no reduction in BK-induced luciferase activity in cells transfected with COX-2 promoter constructs of 674, 407, 239, and 135 bp or constructs with mutated CCAAT/enhancer-binding protein- or NF-kappaB-binding sites. In contrast luciferase activity was reduced in cells transfected with a 407-bp COX-2 promoter fragment containing a mutated cAMP response element (CRE)-binding site, suggesting that the CRE binding site is critical. Electrophoretic mobility shift assays using oligonucleotides specific for the CRE-binding region of the COX-2 promoter and consensus oligonucleotides showed strong specific binding. Furthermore BK increased consensus cAMP-responsive luciferase reporter (p6CRE/luc)-mediated luciferase expression. CRE activation occurred by BK inducing cytosolic phospholipase A2-mediated arachidonic acid release and rapid prostaglandin E2 (PGE2) production, thereby increasing cAMP. Indomethacin inhibited BK-induced PGE2 production, cAMP accumulation, and CRE/luc reporter and COX-2 promoter luciferase activity. Exogenous PGE2 and EP2 (ONO-AE1 259) and EP4 (ONO-AE1 329) PGE2 receptor agonists mimicked the effect of BK. Collectively these studies indicate that COX-2 induction by BK in human pulmonary artery smooth muscle cells is mediated by the CRE through a novel autocrine loop involving endogenous PGE2.
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DOI: 10.1074/jbc.m307964200
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