Objective-Brain expresses abundant lipocalin-type prostaglandin (PG) D 2 (PGD 2 ) synthase but the role of PGD 2 and its metabolite, 15-deoxy-⌬ 12,14 PGJ 2 (15d-PGJ 2 ) in brain protection is unclear. The aim of this study is to assess the effect of 15d-PGJ 2 on neuroprotection. Methods and Results-Adenoviral transfer of cyclooxygenase-1 (Adv-COX-1) was used to amplify the production of 15d-PGJ 2 in ischemic cortex in a rat focal infarction model. Cortical 15d-PGJ 2 in Adv-COX-1-treated rats was increased by 3-fold over control, which was correlated with reduced infarct volume and activated caspase 3, and increased peroxisome proliferator activated receptor-␥ (PPAR␥) and heme oxygenase-1 (HO-1). Intraventricular infusion of 15d-PGJ 2 resulted in reduction of infarct volume, which was abrogated by a PPAR␥ inhibitor. Rosiglitazone infusion had a similar effect. 15d-PGJ 2 and rosiglitazone at low concentrations suppressed H 2 O 2 -induced rat or human neuronal apoptosis and necrosis and induced PPAR␥ and HO-1 expression. The anti-apoptotic effect was abrogated by PPAR␥ inhibition. Key Words: COX-1 Ⅲ 15d-PGJ 2 Ⅲ PPAR␥ Ⅲ apoptosis Ⅲ stroke P rostaglandin (PG) H synthase-1 (also known as cyclooxygenase-1 [COX-1]) is constitutively expressed in almost all mammalian cells. 1 It is a bifunctional enzyme with a cyclooxygenase activity that converts arachidonic acid to PG G 2 (PGG 2 ) and a peroxidase activity that converts PGG 2 to PGH 2 . 2 PGH 2 is converted to diverse prostanoids by specific enzymes. COX-1 plays an important role in maintaining physiological homeostasis and protecting brain tissues from ischemia-reperfusion (I/R) injury. COX-1 deleted mice are highly susceptible to ischemic brain infarction, 3 whereas COX-1 overexpression protects brain from I/R damage, which is abrogated by a selective COX-1 inhibitor. 4 COX-1 overexpression in ischemic brain augments the production of PGI 2 , PGD 2 , and PGE 2 , and suppresses leukotriene B 4 (LTB 4 ) and LTC 4 . As LTB 4 and LTC 4 have been shown to be detrimental to brain tissue, whereas PGI 2 is protective, 5-7 COX-1 overexpression tilts the eicosanoid balance toward tissue protection. PGD 2 is elevated in COX-1 overexpressed brain tissues but its role in brain I/R injury is unclear. Brain is enriched in lipocalin-type PGD synthase (L-PGDS), which catalyzes the formation of abundant PGD 2 . 8 The role of PGD 2 in I/R brain injury is unclear. As 15-deoxy-⌬ 12,14 ; PGJ 2 (15d-PGJ 2 ), a nonenzymatic product of PGD 2 , was shown to possess anti-inflammatory properties through activation of peroxisome proliferator activated receptor-␥ (PPAR␥), 9 -13 PGD 2 has been implicated in tissue protection. However, it has recently been argued that the tissue 15d-PGJ 2 level is too low to elicit an anti-inflammatory action in vivo, especially in vascular tissues. 14 In view of abundant expression of L-PGDS and PGD 2 in brain, we postulated that 15d-PGJ 2 contributes to cerebral protection. Our experimental findings show a considerable amount of 15d-PGJ 2 in ischemia brain, which...
Plasma SCUBE1 concentration is significantly elevated in ACS and AIS but not CAD patients. Plasma SCUBE1 is a potential biomarker of platelet activation in acute thrombotic disease.
Our data suggest that ROS are involved in Ang II-induced proliferation and ET-1 gene expression. Our findings imply that the combination of AT(I) and ET(A) receptor antagonists plus antioxidants may be beneficial in preventing the formation of excessive cardiac fibrosis.
Endothelin-1 (ET-1) has been implicated in fibroblast proliferation. However, the mechanism involving ET-1 is not clear. The present study was performed to examine the role of endogenous ET-1 in ET-1-stimulated fibroblast proliferation and to investigate the regulatory mechanism of ET-1-induced ET-1 gene expression in cardiac fibroblasts. Both ET A receptor antagonistand endothelin-converting enzyme inhibitor (phosphoramidon) inhibited the increased DNA synthesis caused by ET-1. ET-1 gene was induced by ET-1, as revealed with Northern blotting and ET-1 promoter activity assay. ET-1 increased intracellular reactive oxygen species (ROS), which were significantly inhibited by BQ485 and antioxidants. Antioxidants suppressed ET-1 gene expression and DNA synthesis stimulated by ET-1. ET-1 activated mitogen-activated protein kinases (MAPK), including extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase, which were significantly inhibited by antioxidants. Only ERK inhibitor U0126 could inhibit ET-1-induced transcription of the ET-1 gene. Cotransfection of dominant-negative mutant of Ras, Raf, and MEK1 decreased the ET-1-induced increase in ET-1 transcription, suggesting that the Ras-Raf-ERK pathway is required for ET-1 action. Truncation and mutational analysis of the ET-1 gene promoter showed that the activator protein-1 (AP-1) binding site was an important cis-element in ET-1-induced ET-1 gene expression. Antioxidants attenuated the ET-1-stimulated AP-1 binding activity. Our data suggest that ROS were involved in ET-1-induced fibroblast proliferation and mediated ET-1-induced activation of ERK pathways, which culminated in ET-1 gene expression.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.