beraprost and Myocardial-Infarction

Prostacyclin (PGI2) inhibits platelet aggregation and vasoconstriction. PGI2 synthase (PTGIS), a catalyst of PGI2 synthesis from prostaglandin H2, is widely distributed and predominantly found in vascular endothelial and smooth muscle cells. The PTGIS gene is localized to 20q13.11-13 and a candidate gene for cardiovascular disease. We discovered mutations and polymorphisms in this gene and reported that they were associated with essential hypertension, myocardial infarction, and cerebral infarction. These results suggest that PGI2 function depends on the different alleles of the PTGIS gene and that they may influence the risk of cardiovascular disease. Thus, individualized management strategies, such as the administration of PGI2 analogues, could be selected for variants of this gene, to help prevent the development of cardiovascular disease.

Topics: Adult; Aged; Animals; Base Sequence; Cardiovascular Diseases; Cerebral Infarction; Cytochrome P-450 Enzyme System; Epoprostenol; Female; Genetic Predisposition to Disease; Humans; Hypertension; Male; Middle Aged; Molecular Sequence Data; Mutation; Myocardial Infarction; Patient Selection; Pedigree; Phenotype; Platelet Aggregation Inhibitors; Polymorphism, Genetic; Precision Medicine; Risk Factors; Treatment Outcome; Vasodilator Agents

The aim of this study was to elucidate the mechanism of beraprost sodium (BPS) in the intervention of myocardial fibrosis after myocardial infarction (MI) through glycogen synthase kinase-3β (GSK-3β) and to provide new ideas for intervention in myocardial fibrosis.. MI model rats given BPS and cardiac fibroblasts (CFs) treated with BPS and TGF-β. HE staining and Masson staining were used to detect the pathological changes of myocardial tissue. Fibrotic markers were detected by immunohistochemical staining. The expressions of GSK-3β, cAMP response element binding protein (CREB), and p-CREB were analyzed by qPCR and western blot analysis. EDU staining was used to detect the proliferation of CFs. The promoter activity of GSK-3β was detected by luciferase assay. Chromatin immunoprecipitation assay was used to detect the binding levels of GSK-3β promoter and Y-box binding protein 1 (YBX1). The levels of intracellular cyclic adenosine monophosphate (cAMP) were analyzed by enzyme-linked immunosorbent assay (ELISA).. After operation, BPS improved myocardial fibrosis and upregulated GSK-3β protein expression in male SD rats. BPS can down-regulate α-smooth muscle actin (α-SMA) level and up-regulate GSK-3β protein expression in CFs after TGF-β stimulation. Furthermore, GSK-3β knockdown can reverse the effect of BPS on TGF-β-activated CFs, enhance α-SMA expression, and promote the proliferation of CFs. BPS could regulate GSK-3β expression by promoting the binding of GSK-3β promoter to YBX1. BPS induced upregulation of p-CREB and cAMP, resulting in reduced fibrosis, which was reversed by the knockdown of GSK-3β or prostaglandin receptor (IPR) antagonists.. BPS treatment increased the binding of YBX1 to the GSK-3β promoter, and GSK-3β protein expression was upregulated, which further caused the upregulation of p-CREB and cAMP, and finally inhibited myocardial fibrosis.

Topics: Animals; Fibrosis; Glycogen Synthase Kinase 3 beta; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

1. The effects of beraprost sodium (beraprost) on myocardial infarct size in an anesthetized open-chest canine model of regional myocardial ischemia and reperfusion were investigated. 2. Administration of beraprost (300 ng/kg/min, intravenously) to dogs 45 min after left circumflex coronary artery occlusion until 105 min after reperfusion resulted in a significant reduction in infarct size. 3. The values of control and beraprost treated infarct size expressed as a percentage of the total left ventricle were 15 +/- 3% and 4 +/- 2%, respectively. 4. Reperfusion arrhythmia, plasma creatine phosphokinase (CK) and lactate dehydrogenase (LDH) level were significantly suppressed by treatment with beraprost. 5. By histological examination, beraprost proved to reduce neutrophil migration in the ischemic myocardium after 5 h reperfusion. 6. Therefore, it is suggested that the cytoprotective effect of beraprost during myocardial ischemia and reperfusion may be the consequence of the inhibition of neutrophil migration.

Topics: Animals; Arrhythmias, Cardiac; Chemotaxis, Leukocyte; Disease Models, Animal; Dogs; Epoprostenol; Female; Hemodynamics; Leukocyte Count; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Neutrophils; Platelet Aggregation Inhibitors

Platelets play an important role in acute reocclusion after thrombolysis in acute myocardial infarction. We tested a new antiplatelet agent, the stable prostacyclin analogue, beraprost, in the prevention of reocclusion of reperfused vessels with a combination of recombinant tissue-type plasminogen activator (rt-PA) in a canine preparation of coronary artery thrombosis superimposed on high-grade stenosis. Intravenous infusion of rt-PA (17 micrograms/kg/min for 30 min) was combined with beraprost (100, 200 or 300 ng/kg/min for 60 min) or aspirin (35 mg/kg bolus i.v. before rt-PA infusion). The reperfusion time did not differ among the 4 groups. The time from reperfusion to reocclusion (one cycle) in the rt-PA plus beraprost 200 ng/kg/min group was significantly longer than the rt-PA alone group (40 +/- 8 min vs. 9 +/- 2 min, P < 0.05) and the recanalization duration calculated as the mean time from reperfusion to reocclusion in each cycle was prolonged in the rt-PA plus beraprost 200 ng/kg/min group compared with the rt-PA alone group (48 +/- 6 min vs 18 +/- 5 min, P < 0.05) and the reocclusion time and recanalisation duration tended to be elongated in the rt-PA plus beraprost 300 ng/kg/min group, whereas those were not altered by aspirin and 100 ng/kg/min of beraprost. Bleeding time was slightly prolonged and ex vivo platelet aggregation was slightly depressed by beraprost and aspirin. Systemic blood pressure was lowered with higher doses of beraprost. Beraprost sustained coronary reperfusion time and recanalization duration at the higher doses with an optimal level, but could not eliminate reocclusion completely.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aspirin; Coronary Thrombosis; Dogs; Drug Therapy, Combination; Epoprostenol; Myocardial Infarction; Platelet Aggregation Inhibitors; Recurrence; Thrombolytic Therapy; Tissue Plasminogen Activator