beraprost and Cardiovascular-Diseases

Prostacyclin has vasoprotective effects such as vasodilation and antiplatelet aggregatory activity. A relative deficiency of prostacyclin contributes to the pathogenesis of cardiovascular disease including pulmonary artery disease (PAH). Inconvenient intravenous dosing of prostacyclin led to the development of more stable, an orally active analogue: beraprost. It is a chemically stable prostacyclin analogue owing to its cyclo-pentabenzofuranyl structure and produces strong vasodilation and inhibition of platelet aggregation. To date, beraprost has been used in the treatment of PAH and peripheral arterial disease (PAD). Recently, we have shown that beraprost induces neovascularization in ischemic myocardium by enhancement of bone marrow cell mobilization. Interestingly, meta-analysis of clinical studies for PAD has shown that repeated administration of beraprost decreases the number of cardiovascular events. These results suggest that oral administration of beraprost has beneficial effects on cardiovascular disease. Orally active prostacyclin analogues, are promising drugs for the treatment of cardiovascular disease.

Topics: Administration, Oral; Cardiovascular Diseases; Epoprostenol; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Myocardial Ischemia; Neovascularization, Physiologic; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Treatment Outcome; Vasodilator Agents

Beraprost sodium (BPS) is a stable orally active prostacyclin analogue with vasodilatory and anti-platelet effects, and has been widely used as therapeutics for pulmonary artery hypertension and chronic arterial obstruction. In order to elucidate its effects on endothelium, we first examined the short-term effects of BPS on nitric oxide (NO) production and endothelial NO synthase (eNOS) activation using bovine aortic endothelial cells. Short-term treatment of BPS induced NO production as well as eNOS phosphorylation at Ser-1179 mediated via cAMP/protein kinase A (PKA) pathway. The effects of BPS on capillary-like tube formation were next determined using human umbilical vein ECs (HUVECs)/normal human dermal fibroblasts co-culture system. BPS was observed to induce capillary-like tube formation mediated via cAMP/PKA pathway, but not via NO generation. Finally, we performed DNA microarray analyses using RNA extracted from BPS treated HUVECs. Interestingly, BPS up-regulated several genes involved in angiogenesis, anti-atherosclerosis, and endothelial function, while down-regulated several genes involved in atherosclerosis. Our data therefore indicate that BPS may be useful not only for patients with pulmonary artery hypertension and chronic arterial obstruction, but also for general atherosclerotic patients complicated with endothelial dysfunction. Further studies are needed to clarify molecular mechanisms of these BPS effects including the involvement of peroxisome proliferator-activated receptor-delta.

Topics: Animals; Arterial Occlusive Diseases; Atherosclerosis; Cardiovascular Diseases; Endothelium, Vascular; Epoprostenol; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Neovascularization, Physiologic; Nitric Oxide; Nitric Oxide Synthase Type III; Platelet Aggregation Inhibitors; Signal Transduction; Vasodilator Agents

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

To investigate the current status of peripheral arterial disease (PAD) drug treatment in Japan, and the effects of drug treatment, risk factors, and complications on disease progress and onset of cardiovascular events in PAD patients.. In this prospective observational cohort study, 557 PAD patients were followed up for 3 years, and the current status of PAD treatment, risk factors, and cardiovascular events were monitored.. Three drugs, i.e., beraprost sodium, cilostazol, and aspirin, were most frequently used. The patients who had undergone vascular reconstruction of the lower limbs before enrollment showed significant improvement in ABI. Among the patients who had not undergone vascular reconstruction before enrollment, there was a significant improvement in ABI after treatment with beraprost. During the observation period, cardiovascular deaths occurred in 35 patients (6.3%), heart diseases in 63 (11.3%), brain diseases in 39 (7.0%), and events in the lower limbs in 94 (16.9%). The factors affecting the increase of the cardiovascular events were explored by multivariate analysis (Cox regression analysis). As a result, age (75 years or older), ischemic heart disease and increase in severity on the Fontaine classification were identified as significant factors for cardiovascular deaths, whereas kidney disorders and increase in severity on the Fontaine classification were identified for heart diseases, the number of oral drugs for treating PAD was identified for brain diseases, and age (younger than 75 years), dialysis, ABI (less than 0.7) and aspirin were identified for the events in the lower limbs.. As a result of the three-year follow-up on the Japanese PAD cohort, the current status of PAD treatment, risk factors, and cardiovascular events could be identified.

Topics: Adult; Aged; Aged, 80 and over; Ankle Brachial Index; Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Cilostazol; Disease Progression; Epoprostenol; Female; Follow-Up Studies; Humans; Japan; Male; Middle Aged; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Quality of Life; Risk Assessment; Risk Factors; Severity of Illness Index; Societies, Medical; Tetrazoles; Time Factors; Treatment Outcome; Vascular Surgical Procedures; Vasodilator Agents