beraprost and Cardiomyopathies

Doxorubicin (DOX) is widely used as an anti-cancer agent although it causes irreversible cardiomyopathy by increasing oxidative stress and deregulating nitric oxide production. Beraprost (BPS), a stable prostacyclin (PGI2) analog, is a potent vasodilator that has beneficial effects on myocardial ischemia. The objectives of the present study were to delineate the uncertain effects of prostcyclin therapy on DOX induced cardiomyopathy and to explore the mechanisms underlying PGI2 and DOX interaction. For this reason, we stimulated endogenous PGI2 production using bicistronic COX-1/PGIS gene transfer and BPS supplementation, and investigated the effects on DOX-induced cardiomyopathy. Caspase-dependent protein content, lactate dehydrogenase (LDH), DNA fragmentation, and TUNEL positive cells were elevated in DOX-treated cardiomyocytes. These indicators were further elevated by adenovirus-COX- 1/PGIS transfection or BPS supplementation. In addition, PGI2 overexpression further increased iNOS expression and superoxide accumulation in cardiomyocytes compared with DOX alone, which may be the reason for aggravated cytotoxicity. Moreover, BPS can induce cAMP response elements (CRE) binding to the iNOS promoter and phospho- cAMP response element binding protein (CREB) expression in a cyclic AMP-dependent manner. Our in vivo studies show that MnTBAP and aminoguanidine treatment of DOX and BPS co-administered in mice can attenuate caspase-3 and PARP-1 protein expression, and improve mouse survival, as observed in the iNOS gene-deleted mice. In conclusion, we demonstrated that BPS or adv-COX-1/PGIS increases PGI2 levels through iNOS expression and peroxynitrite production, via CREB protein phosphorylation; thereby aggravating DOX-mediated cardiotoxicity.

Topics: Animals; Apoptosis; Cardiomyopathies; CREB-Binding Protein; Cyclooxygenase 1; Doxorubicin; Epoprostenol; Male; Mice; Mice, Inbred C57BL; Myocardial Ischemia; Myocytes, Cardiac; Nitric Oxide Synthase Type II; Peroxynitrous Acid; Phosphorylation; Prostaglandins; Rats; Rats, Wistar

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

We examined whether beraprost sodium (beraprost), a stable prostacyclin analogue, prevented cardiomyopathy in diabetic rats in vivo. Diabetes was induced by a bolus injection of streptozotocin in rat-tail vein. Four weeks after the induction of diabetes, the animals were treated with beraprost (30 micrograms/kg/day, p.o.) for 4 weeks until they were used for the measurement of hemodynamics, electrocardiogram (ECG), and plasma creatine phosphokinase (CK) activity. Nontreated diabetic rats have lower mean blood pressure, heart rate, left ventricular systolic pressure, and peak positive dP/dt at basal levels compared to age-matched normal rats. All of these changes were not improved in beraprost-treated rats. The left ventricular end-diastolic pressure and ST/R ratio in the ECG were significantly increased in diabetic rats. These parameters were significantly improved by beraprost compared with nontreated diabetic rats. Additionally, beraprost significantly suppressed the elevation of plasma CK activity as compared with that in non-treated diabetic rats. Changes in peak positive dP/dt in response to isoproterenol were attenuated in nontreated diabetic rats as compared with age-matched normal rats and beraprost-treated diabetic rats. These results suggest that beraprost is capable of preventing diabetic cardiomyopathy without affecting hyperglycemic condition.

Topics: Administration, Oral; Animals; Blood Glucose; Blood Pressure; Body Weight; Cardiomyopathies; Creatine Kinase; Diabetes Mellitus, Experimental; Electrocardiography; Epoprostenol; Heart Rate; Male; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Streptozocin; Ventricular Function, Left