beraprost and Fibrosis

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

Beraprost sodium (BPS), as a prostacyclin analog, plays a significant role in various diseases based on its antiplatelet and vasodilation functions. However, its regulation and role in chronic kidney disease (CKD) still remain elusive. Here, we determined whether BPS could alleviate renal interstitial fibrosis, and improve the renal function and its therapeutic mechanism. In vitro, BPS increased angiogenesis in the HUVECs incubated with BPS detected by tube formation assay and repair damaged endothelial cell-cell junctions induced by hypoxia. In vivo, mice were randomly assigned to a sham-operation group (sham), a unilateral ureteral obstruction group (UUO), and a BPS intragastrical administration group (BPS), and sacrificed at days 3 and 7 post-surgery (six in each group). In UUO model, tissue hypoxia, renal inflammation, oxidative stress, and fibrotic lesions were detected by q-PCR and Western blot techniques and peritubular capillaries (PTCs) injury was detected by a novel technique of fluorescent microangiography (FMA) and analyzed by MATLAB software. Meanwhile, we identified cells undergoing endothelial cell-to-myofibroblast transition by the coexpression of endothelial cell (CD31) and myofibroblast (a-SMA) markers in the obstructed kidney. In contrast, BPS protected against interstitial fibrosis and substantially reduced the number of endothelial cell-to-myofibroblast transition cells. In conclusion, our data indicate the potent therapeutic of BPS in mitigating fibrosis through repairing renal microvessels and suppressing endothelial-mesenchymal transition (EndMT) progression after inhibiting inflammatory and oxidative stress effects. KEY MESSAGES: BPS could improve renal recovery through anti-inflammatory and anti-oxidative pathways. BPS could mitigate fibrosis through repairing renal microvessels and suppressing endothelial-mesenchymal transition (EndMT).

Topics: Adult; Animals; Chemokine CCL2; Disease Models, Animal; Epoprostenol; Fibrosis; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-6; Kidney; Kidney Function Tests; Male; Mice, Inbred C57BL; Microvessels; Neovascularization, Physiologic; Regeneration; Transforming Growth Factor beta; Tyrosine; Uncoupling Protein 2; Ureteral Obstruction; Vascular Endothelial Growth Factor A

Beraprost sodium (BPS) is an orally active prostacyclin analogue. The effects of BPS on the heart, including coronary circulation improvement, myocardial and vascular protection and anti-fibrosis effect on myocardium interstitium, have previously been demonstrated. However, the effects of BPS on hemodynamics, cardiac function and myocardial contractility in patients in the hypertrophic phase have not been clarified. Therefore, in the present study, the effects of BPS under long-term administration were investigated using the hypertension model of salt-sensitive Dahl rats. Six-week-old Dahl rats were divided into three groups, an 8% high salt diet group treated with BPS (BPS group), an untreated 8% high salt diet group (HHF group) and an untreated 0.3% low salt diet group (Control group), and observations were conducted until 17 weeks of age. In the BPS and HHF groups, the survival rates after 11 weeks of high salt diet intake were 87.5% and 47.1%, respectively (p<0.05). At 17 weeks of age, the atrial systolic peak velocity/early diastolic peak velocity and heart weight index of the BPS group decreased significantly compared with the HHF group (p<0.05). The HHF group exhibited significantly more severe myocardial fibrosis mainly in the endocardial layer of the left and right ventricles compared with the BPS and Control groups (p<0.05). In the present study, long-term BPS administration preserved diastolic function and prevented myocardial interstitial fibrosis in the non-compensatory phase. The results of the present study suggest that BPS is effective for treatment of hypertensive cardiac hypertrophy.

Topics: Animals; Cardiomyopathies; Drug Administration Schedule; Endocardium; Epoprostenol; Fibrosis; Heart Failure; Heart Function Tests; Heart Ventricles; Longevity; Rats; Rats, Inbred Dahl; Vasodilator Agents

This study investigated the effect of prostaglandin I2 analogue (TRK-100) on the healing of arterial anastomoses. The infrarenal abdominal aorta was divided and reanastomosed immediately in rabbits. A control group of rabbits were fed commercial rabbit food (ORC 4); a cholesterol group of rabbits were fed a diet with 1% cholesterol added to ORC 4; and a TRK group of rabbits received the same diet as the cholesterol group, but TRK-100 was given subcutaneously at a dose of 0.3 mg (TRK-I group) or 1.0 mg (TRK-II group) every other day. After 3 months a blood sample was taken for biochemical analysis, and the abdominal aorta was harvested for histologic examination. The serum lipid and thromboxane B2 concentrations and the thromboxane B2/6-keto prostaglandin F1 alpha ratio in the TRK groups were significantly lower than in the cholesterol group. The proliferative connective tissue did not cover the anastomotic suture line in either the control or the TRK groups. However, the suture line was covered completely by connective tissue in the cholesterol group. Intimal thickness in the cholesterol group was greater than in either the control or the TRK-II group (p less than 0.01 and p less than 0.05, respectively). These data suggest that TRK-100 may suppress intimal fibrous proliferation at anastomotic suture lines by a mechanism affecting the thromboxane B2/6-keto prostaglandin F1 alpha ratio.

Topics: Analysis of Variance; Anastomosis, Surgical; Animals; Aorta, Abdominal; Blood Platelets; Cell Division; Cholesterol; Cholesterol, Dietary; Epoprostenol; Fibrosis; Male; Platelet Aggregation Inhibitors; Rabbits