Vascular Endothelial Growth Factor- and Thrombin-induced Termination Factor, Down Syndrome Critical Region-1, Attenuates Endothelial Cell Proliferation and Angiogenesis

Minami, Takashi; Horiuchi, Keiko; Miura, Mai; Abid, M. Ruhul; Takabe, Wakako; Noguchi, Noriko; Kohro, Takahide; Ge, Xijin; Aburatani, Hiroyuki; Hamakubo, Takao; Kodama, Tatsuhiko; Aird, William C.

doi:10.1074/jbc.m406454200

Cited by 218 publications

(313 citation statements)

References 44 publications

(37 reference statements)

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“…Moreover, cysLT 2 -R may signal through the Ca 2ϩ ͞calmodulin͞calcineurin͞ NFAT pathway, as evidenced by the potent inhibitory action of the immunosuppressant, i.e., cyclosporin, on LTD 4 -triggered DSCR1 transcript up-regulation that we observed in three independent experiments (data not shown). It is noteworthy that DSCR1 may provide a major endogenous feedback inhibitor of NFAT signaling of inflammation in T cells and HUVECs by other GPCR and non-GPCR activation events (31,(34)(35)(36). Several genes up-regulated in response to cysLT 2 -R activation and studied here in detail are up-regulated in HUVECs by other GPCRs, such as the major HUVEC thrombin receptor (PAR-1) or the histamine receptor (46) in a cyclosporin-sensitive manner (31,34,46).…”

Section: Discussionmentioning

confidence: 99%

“…It is noteworthy that DSCR1 may provide a major endogenous feedback inhibitor of NFAT signaling of inflammation in T cells and HUVECs by other GPCR and non-GPCR activation events (31,(34)(35)(36). Several genes up-regulated in response to cysLT 2 -R activation and studied here in detail are up-regulated in HUVECs by other GPCRs, such as the major HUVEC thrombin receptor (PAR-1) or the histamine receptor (46) in a cyclosporin-sensitive manner (31,34,46). Thus, several of the early genes may be the result of G q protein coupling, but additional G proteins may also be involved (6).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, two LTD 4 -responsive genes have established antiinflammatory actions, i.e., COX-2 (data not shown) and DSCR1 ( Fig. 7): COX-2 is a key prostacyclin-synthesisregulating enzyme in ECs (33), and DSCR1 has been shown to strongly down-regulate proinflammatory calcineurin͞nuclear factor of activated T cells (NFAT)-transactivated genes by directly inhibiting calcineurin (31,(34)(35)(36). In preliminary studies, we observed marked up-regulation of COX-2 protein and prostacyclin formation (K.L.…”

Section: Ltd4 Stimulates Expression Of Genes Implicated In Ec Activatmentioning

confidence: 99%

“…We chose additional genes implicated in EC-activation regulation for detailed analyses, i.e., E-selectin (SELE), a disintegrin-like and metalloprotease with thrombospondin type 1 motif 1 (ADAMTS1), Down syndrome critical region gene 1 (DSCR1), CXCL2 (MIP2), and CXCL8 (IL-8) (28)(29)(30)(31)(32). SELE, ADAMTS1, and DSCR1 transcripts peaked Ϸ60 min and then declined but remained elevated for 6 h (Fig.…”

Section: Ltd4 Stimulates Expression Of Genes Implicated In Ec Activatmentioning

confidence: 99%

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Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells

Uzonyi

Lötzer

Jahn

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Cysteinyl leukotrienes (cysLT), i.e., LTC4, LTD4, and LTE4, are lipid mediators derived from the 5-lipoxygenase pathway, and the cysLT receptors cysLT 1-R͞cysLT2-R mediate inflammatory tissue reactions. Although endothelial cells (ECs) predominantly express cysLT 2-Rs, their role in vascular biology remains to be fully understood. To delineate cysLT2-R actions, we stimulated human umbilical vein EC with LTD 4 and determined early induced genes. We also compared LTD4 effects with those induced by thrombin that binds to protease-activated receptor (PAR)-1. Stringent filters yielded 37 cysLT 2-R-and 34 PAR-1-up-regulated genes (>2.5-fold stimulation). Most LTD4-regulated genes were also induced by thrombin. Moreover, LTD4 plus thrombin augmented gene expression when compared with each agonist alone. Strongly induced genes were studied in detail: Early growth response (EGR) and nuclear receptor subfamily 4 group A transcription factors; E-selectin; CXC ligand 2; IL-8; a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1 (ADAMTS1); Down syndrome critical region gene 1 (DSCR1); tissue factor (TF); and cyclooxygenase 2. Transcripts peaked at Ϸ60 min, were unaffected by a cysLT 1-R antagonist, and were superinduced by cycloheximide. The EC phenotype was markedly altered: LTD 4 induced de novo synthesis of EGR1 protein and EGR1 localized in the nucleus; LTD4 up-regulated IL-8 formation and secretion; and LTD4 raised TF protein and TF-dependent EC procoagulant activity. These data show that cysLT 2-R activation results in a proinflammatory EC phenotype. Because LTD 4 and thrombin are likely to be formed concomitantly in vivo, cysLT 2-R and PAR-1 may cooperate to augment vascular injury.cysteinyl leukotriene 2 receptor gene signature ͉ protease-activated receptor 1 gene signature ͉ vascular inflammation L eukotrienes (LTs), i.e., LTB 4 and the cysteinyl LTs (cysLT) LTC 4 , LTD 4 , and LTE 4 constitute a group of lipid mediators derived from the 5-lipoxygenase (5-LO) pathway (1, 2). LTs are either produced by leukocytes at sites of inflammation or formed through transcellular metabolism after uptake and metabolism of leukocyte-derived LTA 4 by downstream enzymes of the 5-LO pathway (LTA 4 hydrolase and LTC 4 synthase) in cells that normally do not express 5-LO, such as endothelial cells (ECs) (3, 4). LTs act through G protein-coupled surface receptors (GPCRs), i.e., the LTB 4 receptors and the cysLT receptors (LT-Rs) (cysLT 1 -R and cysLT 2 -R) (5-10). LT-Rs are expressed on multiple target cells, including leukocytes, smooth muscle cells, and ECs (1). Recent studies implicate the 5-LO pathway in cardiovascular disease (11)(12)(13)(14)(15)(16)(17).Considerable information is available on cysLT 1 -R, whereas little is known about cysLT 2 -R. We have used human umibilical vein (HUV)ECs as a model of vascular cells to study cysLT 2 -R activation by demonstrating that cysLTs exclusively signal through cysLT 2 -R in this cell type (18): In fact, HUVECs are the first primary cell type that s...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ltd4 Stimulates Expression Of Genes Implicated In Ec Activatmentioning

confidence: 99%

Section: Ltd4 Stimulates Expression Of Genes Implicated In Ec Activatmentioning

confidence: 99%

See 2 more Smart Citations

Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells

Uzonyi

Lötzer

Jahn

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, endostatin and related DS genes have been shown to downregulate VEGF signaling through inhibition of calciumcalcineurin NF-AT (nuclear factor of activated T cells) activities, which attenuate endothelial proliferation and angiogenesis. [137][138][139][140][141][142][143] Whereas these factors may be beneficial for protecting against tumor angiogenesis, we hypothe- . Three-dimensional reconstruction of distal lung tissue, illustrating intrapulmonary arteriovenous communications ("shunt vessels") in infant with severe bronchopulmonary dysplasia (BPD).…”

Section: Pvd In Bpdmentioning

confidence: 99%

The Robyn Barst Memorial Lecture: Differences between the Fetal, Newborn, and Adult Pulmonary Circulations: Relevance for Age‐Specific Therapies (2013 Grover Conference Series)

et al. 2014

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Pulmonary arterial hypertension (PAH) contributes to poor outcomes in diverse diseases in newborns, infants, and children. Many aspects of pediatric PAH parallel the pathophysiology and disease courses observed in adult patients; however, critical maturational differences exist that contribute to distinct outcomes and therapeutic responses in children. In comparison with adult PAH, disruption of lung vascular growth and development, or angiogenesis, plays an especially prominent role in the pathobiology of pediatric PAH. In children, abnormalities of lung vascular development have consequences well beyond the adverse hemodynamic effects of PAH alone. The developing endothelium also plays critical roles in development of the distal airspace, establishing lung surface area for gas exchange and maintenance of lung structure throughout postnatal life through angiocrine signaling. Impaired functional and structural adaptations of the pulmonary circulation during the transition from fetal to postnatal life contribute significantly to poor outcomes in such disorders as persistent pulmonary hypertension of the newborn, congenital diaphragmatic hernia, bronchopulmonary dysplasia, Down syndrome, and forms of congenital heart disease. In addition, several studies support the hypothesis that early perinatal events that alter lung vascular growth or function may set the stage for increased susceptibility to PAH in adult patients ("fetal programming"). Thus, insights into basic mechanisms underlying unique features of the developing pulmonary circulation, especially as related to preservation of endothelial survival and function, may provide unique therapeutic windows and distinct strategies to improve short-and long-term outcomes of children with PAH.Keywords: pulmonary vascular development, angiogenesis, alveolarization, persistent pulmonary hypertension of the newborn, congenital diaphragmatic hernia, bronchopulmonary dysplasia, Down syndrome, pediatric pulmonary hypertension. Pulmonary arterial hypertension (PAH) is a devastating and progressive disease that is characterized by abnormalities of vascular tone and reactivity, vessel wall structure, growth, and thrombosis. 1 Mechanisms contributing to PAH and its progression are complex and remain incompletely understood. Insights into vascular biology over the past few decades have led to remarkable improvements in the clinical course, outcomes, and survival in adults with PAH, yet relatively few studies have been performed in children. As in adults, PAH contributes to poor outcomes in diverse cardiac, pulmonary, and systemic diseases in newborns, infants, and children (Table 1). 2 There is a clear need to define the natural history of pediatric PAH in diverse settings; to develop new strategies to identify at-risk patients early in their course; and to establish novel approaches to better diagnose, evaluate, and treat children with PAH. 3,4 Despite many similarities between pediatric and adult PAH, critical differences exist that currently limit our clinical appr...

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Upregulation of RCAN1.4 by HIF1α alleviates OGD‐induced inflammatory response in astrocytes

Yang

Yun

Wang

et al. 2022

Ann Clin Transl Neurol

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Objective: Ischemic stroke is a leading cause of human mortality and longterm disability worldwide. As one of the main forms of regulator of calcineurin 1 (RCAN1), the contribution of RCAN1.4 in diverse biological and pathological conditions has been implicated. But the role of RCAN1.4 in ischemic stroke progression remains elusive. This study is to explore the expression changes and roles of RCAN1.4 in ischemic stroke as well as the underlying mechanisms for these changes and effects of RCAN1.4 in ischemic stroke. Methods: Middle cerebral artery occlusion model in C57BL/6J mice and oxygen-glucose deprivation (OGD) model in primary astrocytes were performed to induce the cerebral ischemic stroke. The expression pattern of RCAN1.4 was assessed using realtime quantitative PCR and western blotting in vivo and in vitro. Mechanistically, the underlying mechanism for the elevation of RCAN1.4 in the upstream was investigated. Lentiviruses were administrated, and the effect of RCAN1.4 in postischemic inflammation was clearly clarified. Results: Here we uncovered that RCAN1.4 was dramatically increased in mouse ischemic brains and OGDinduced primary astrocytes. HIF1a, activated upon OGD, significantly upregulated RCAN1.4 gene expression through specifically binding to the RCAN1.4 promoter region and activating its promoter activity. The functional hypoxiaresponsive element (HRE) was located between À254 and À245 bp in the RCAN1.4 promoter region. Moreover, elevated RCAN1.4 alleviated the release of pro-inflammatory cytokines TNFa, IL1b, IL6 and reduced expression of iNOS, COX2 in primary astrocytes upon OGD, whereas RCAN1.4 silencing has the opposite effect. Of note, RCAN1.4 overexpression inhibited OGD-induced NF-jB activation in primary astrocytes, leading to decreased degradation of IjBa and reduced nuclear translocation of NF-jB/p65. Interpretation: Our results reveal a novel mechanism underscoring the upregulation of RCAN1.4 by HIF1a and the protective effect of RCAN1.4 against postischemic inflammation, suggesting its significance as a promising therapeutic target for ischemic stroke treatment.

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Vascular Endothelial Growth Factor- and Thrombin-induced Termination Factor, Down Syndrome Critical Region-1, Attenuates Endothelial Cell Proliferation and Angiogenesis

Cited by 218 publications

References 44 publications

Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells

Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells

The Robyn Barst Memorial Lecture: Differences between the Fetal, Newborn, and Adult Pulmonary Circulations: Relevance for Age‐Specific Therapies (2013 Grover Conference Series)

Upregulation of RCAN1.4 by HIF1α alleviates OGD‐induced inflammatory response in astrocytes

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