Effects of a stable prostacyclin analogue beraprost sodium on VEGF and PAI-1 gene expression in vascular smooth muscle cells

Atsuta, Hiroyuki; Uchiyama, Tsuyoshi; Kanai, Hiroyuki; Iso, Tatsuya; Tanaka, Toru; Suga, Tatsuo; Maeno, Toshitaka; Arai, M.; Nagai, Ryozo; Kurabayashi, Masahiko

doi:10.1016/j.ijcard.2007.12.119

Cited by 10 publications

(11 citation statements)

References 28 publications

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“…In addition to inhibiting platelet aggregation, PGI 2 may inhibit thrombosis by inhibiting coagulation factors Va, VIIIa (Rabausch et al, 2005), tissue factor (Crutchley et al, 1992), and other proteins involved in coagulation, such as PAI-1 (Atsuta et al, 2009), von Willebrand factor, and D-dimer ). Iloprost and cicaprost increase mRNA expression and protein amount of thrombomodulin, which binds to thrombin with high affinity, resulting in activation of protein C, which in turn proteolytically degrades factors Va and VIIIa, thus inhibiting further thrombin generation and blood coagulation (Rabausch et al, 2005).…”

Section: B the Prostacyclin Pathway And Blood Coagulationmentioning

confidence: 99%

“…PGI 2 induces VEGF production in a human monocytic cell line and increases VEGF gene expression in isolated rat lung and rat aortic VSMCs (Pola et al, 2004). Beraprost augments hypoxia-induced VEGF mRNA expression in cultured aortic VSMCs through PKA/CREB-dependent mechanisms (Atsuta et al, 2009). The angiogenic property of PGI 2 mediated by VEGF may involve PGI 2 binding to nuclear PPAR receptors because only PGI 2 analogs that act as PPARs ligands, such as iloprost and carbacyclin, but not cicaprost, are able to induce angiogenesis in murine cornea (Pola et al, 2004).…”

Section: The Prostacyclin Pathway and Angiogenesismentioning

confidence: 99%

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Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

2012

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Section: B the Prostacyclin Pathway And Blood Coagulationmentioning

confidence: 99%

Section: The Prostacyclin Pathway and Angiogenesismentioning

confidence: 99%

Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

2012

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“…PAI-1 blocks fibrinolysis by inhibiting plasminogen activator and VN stabilizes the active form of PAI-1 [18, 19]. Deletion of PAI-1 or VN in wild type mice delays thrombotic occlusion in arterial injury [21].…”

Section: Resultsmentioning

confidence: 99%

“…There are several other lines of evidence that support the suggestion that decreased PGI 2 production mediates the elevated PAI-1 levels and the shortened time to occlusion associated with the COX-1 +/− COX-2 −/− genotype. Stable analogs of PGI 2 decrease PAI-1 expression in vascular smooth muscle cells (18, 19). Moreover, the administration of iloprost, a stable analog of PGI 2 , to diabetic patients resulted in diminished PAI-1 activity (20).…”

Section: Discussionmentioning

confidence: 99%

“…Although the role of cyclooxygenase products in coagulation has been extensively investigated, their role in clot resolution or fibrinolysis is largely unexplored. Incubation of stable PGI 2 analogs with vascular smooth muscle cells in culture results in a decreased expression of plasminogen activator inhibitor 1 (PAI-1), a protein that decreases fibrinolysis by inhibiting both tissue-type plasminogen activator and urokinase-type plasminogen activator and thus plasmin formation [18,19]. Treatment of diabetic patients with iloprost, a stable PGI 2 analog, results in decreased plasma PAI-1 activity [20].…”

Section: Introductionmentioning

confidence: 99%

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COX‐1+/−COX‐2−/− genotype in mice is associated with shortened time to carotid artery occlusion through increased PAI‐1

Riehl

He²,

Zheng³

et al. 2011

Journal of Thrombosis and Haemostasis

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Summary. Background: We found a high incidence of thrombotic deaths in COX‐1+/−COX‐2−/− mice and sought to define the mechanism of these events. The cyclooxygenase products thromboxane A2 and prostacyclin are important in the regulation of coagulation but their role in fibrinolysis is largely unexplored. PAI‐1 blocks fibrinolysis by inhibiting plasminogen activator. Aim: Our objective was to explain the mechanism of increased thrombosis associated with the COX‐1+/−COX‐2−/− genotype. Methods: Carotid artery occlusion times were measured after photochemical injury. PAI‐1 levels were measured in the plasma by ELISA. PAI‐1 levels in the aorta were measured by RT‐PCR and Western blotting. Urinary metabolites of Thromboxane A2 and prostacyclin were measured by ELISA. Results: The COX‐1+/−COX‐2−/− genotype is associated with a decreased time to occlusion in the carotid artery thrombosis model (30 ± 5 minutes vs 60 ± minutes in wild type, p<.001). The COX‐1−/−COX‐2+/+, COX‐1+/−COX‐2+/− and COX‐1+/− COX‐2+/+ all had occlusion times similar to wild type. COX‐1+/+ COX‐2−/− had a prolonged occlusion time. COX‐1+/− COX‐2−/− had increased PAI‐1 levels in the plasma and aorta and with a prolonged euglobulin lysis time (37.4 ± 10.2 hours vs 15.6 ± 9.8 hours in wild type, p<.004). The decreased time to occlusion in the COX‐1+/−COX2−/− mice was normalized by an inhibitory antibody to PAI‐1 whereas the antibody had no effect on the time to occlusion in wild type mice. Conclusion: The COX‐1+/−COX‐2−/− genotype is associated with a shortened time to occlusion in the carotid thrombosis model and the shortened time to occlusion is mediated through increased PAI‐1 levels resulting in decreased fibrinolysis.

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Acute and long-term effects of inhaled iloprost in portopulmonary hypertension

et al. 2010

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Portopulmonary hypertension (PoPH) is a serious condition without an established treatment. Drugs used to treat pulmonary hypertension may have detrimental effects on portal hypertension. This study was designed to assess in patients with PoPH the acute effects of inhaled iloprost (iILO) on pulmonary and hepatic hemodynamics and to evaluate the clinical outcome after 12 months of treatment. We conducted 2 separate studies. In the first one, 21 patients with PoPH were acutely tested with 2.8 lg of iILO. Pulmonary and hepatic hemodynamics were assessed at the baseline and through 60 minutes after iILO. In the second one, we retrospectively evaluated 12 patients treated with iILO (30 lg/day) for more than 1 year. The 6-minute walk distance (6MWD), functional class (FC), and echocardiogram were analyzed at the baseline and after 12 months of treatment. In the acute study, iILO rapidly reduced pulmonary artery pressure (PAP; À16% 6 8%, P < 0.001) and pulmonary vascular resistance (À18% 6 14%, P < 0.001). The cardiac output did not change initially but decreased after 30 minutes. The hepatic venous pressure gradient (HVPG) and hepatic blood flow did not vary through the study. Pulmonary vasodilation induced by iILO was inversely related to HVPG. In the long-term evaluation, iILO improved FC by 1 or more in 7 patients (P ¼ 0.04) and increased 6MWD by 67 6 59 m at 12 months (P < 0.001). No change in systolic PAP was observed. Two patients died because of hepatic complications, and 4 additional patients presented clinically significant events that were related to hepatic disease in 2 and worsening of pulmonary hypertension in 2. We conclude that in patients with PoPH, iILO produces rapid and selective pulmonary vasodilation without altering the hepatic hemodynamics. Its long-term use may provide sustained improvements in symptoms and exercise tolerance in some patients with PoPH. A randomized, controlled trial is warranted to establish its clinical role in this serious condition.

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Effects of a stable prostacyclin analogue beraprost sodium on VEGF and PAI-1 gene expression in vascular smooth muscle cells

Cited by 10 publications

References 28 publications

Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

COX‐1+/−COX‐2−/− genotype in mice is associated with shortened time to carotid artery occlusion through increased PAI‐1

Acute and long-term effects of inhaled iloprost in portopulmonary hypertension

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