cardiovascular-agents and succinobucol

The phenotype shifting of vascular smooth muscle cells (VSMCs) was indicated to play a role during the initial stage of atherosclerotic plaque formation by facilitating extracellular matrix deposition. This study was aimed at investigating the involvement of the apoptosis signal-regulating kinase 1 (ASK1) /mitogen-activated protein kinase (MAPK) kinases (MKKs) /p38 MAPK pathway in the advanced glycation end product (AGE) -induced fibrotic response of VSMCs. The effect of the novel ASK1 inhibitor AGI-1067 was also studied.Cultured human coronary smooth muscle cells (HCSMCs) were exposed to AGEs. AGI-1067 and siRNAs silencing mkk3, mkk6, and p38 mapk were used to treat the cells. The activation of MKK3, MKK6, and p38 MAPK was assessed by immunoblotting. Fibrotic response was assessed by the fluorescence immunohistochemistry staining of collagen I and collagen VIII. Activation of immunoprecipitation determined the association of ASK1 and its inhibitor thioredoxin. A kinase assay was used to determine ASK1 activity.AGE incubation significantly activated ASK1, MKK3, and MKK6, which led to activation of p38 MAPK, resulting in upregulated fibrotic response in HCSMCs. However, siRNAs knocking down mkk3, mkk6, and p38 mapk impaired this fibrotic response. AGI-1067 administration not only dramatically inhibited the activation of ASK1/MKKs/p38 MAPK but also suppressed the expression of the downstream proteins, including transforming growth factor-β1, connective tissue growth factor, collagen I, and collagen VIII in HCSMCs exposed to AGEs.The ASK1/MKKs/p38 MAPK pathway was activated by AGEs, leading to the fibrotic response in VSMCs. AGI-1067 reversed this process by maintaining the inactive state of ASK1.

Topics: Blotting, Western; Cardiovascular Agents; Cells, Cultured; Coronary Vessels; Fibrosis; Glycation End Products, Advanced; Humans; Immunoprecipitation; MAP Kinase Kinase 3; MAP Kinase Kinase 6; MAP Kinase Kinase Kinase 5; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; p38 Mitogen-Activated Protein Kinases; Probucol; Signal Transduction

The aim of this study was to assess the efficacy of stent-based delivery of succinobucol alone and in combination with rapamycin in a porcine coronary model.. Current drugs and polymers used to coat coronary stents remain suboptimal in terms of long term efficacy and safety. Succinobucol is a novel derivative of probucol with improved antioxidant and anti-inflammatory properties.. Polymer-free Yukon stents were coated with 1% succinobucol (SucES), 2% rapamycin (RES), or 1% succinobucol plus 2% rapamycin solutions (SucRES) and compared with a bare metal stent (BMS).. The in vivo release profile of SucES indicated drug release up to 28 days (60% drug released at 7 days); 41 stents (BMS, n = 11; SucES, n =10; RES, n = 10; SucRES, n = 10) were implanted in the coronary arteries of 17 pigs. After 28 days, mean neointimal thickness was 0.31 ± 0.14 mm for BMS, 0.51 ± 0.14 mm for SucES, 0.19 ± 0.11 mm for RES, and 0.36 ± 0.17 mm for SucRES (P < 0.05 for SucES vs. BMS). SucES increased inflammation and fibrin deposition compared with BMS (P < 0.05), whereas RES reduced inflammation compared with BMS (P < 0.05).. In this model, stent-based delivery of 1% succinobucol using a polymer-free stent platform increased neointimal formation and inflammation following coronary stenting.

Topics: Animals; Cardiovascular Agents; Cattle; Cell Survival; Cells, Cultured; Coronary Vessels; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug-Eluting Stents; Endothelial Cells; Fibrin; Inflammation; Male; Metals; Models, Animal; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Percutaneous Coronary Intervention; Probucol; Prosthesis Design; Sirolimus; Swine

Cardiovascular diseases remain a major cause of morbidity and mortality worldwide, regardless of the recent advances in medical and surgical treatment, for as life expectancy in the developed countries increases, cardiovascular conditions affecting the elderly also rises. Atherosclerosis and cardiovascular diseases take a huge toll on the society, making them the leading cause of death in developed countries. Phenomenal advances in the pathophysiology of cardiovascular disease and the molecular signaling pathways has revealed the role of endothelial dysfunction involved therein and thus has raised the possibility of novel therapeutic targets. Such potential cellular targets include the vascular smooth muscle cells, monocyte/macrophage cell lines, platelets, and endothelial cells. Certain studies affirm that antiplatelet agents, antioxidant therapies, amino acid supplementation, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers may prevent or slow the progression of the disease process. The race is on for new medicines that can treat and prevent heart attacks and strokes, arising out of atherosclerosis, which kills nearly 1 million people a year in the U.S.A alone.

Topics: Anticholesteremic Agents; Benzaldehydes; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Endothelin Receptor Antagonists; Fibrinolytic Agents; Humans; Immunologic Factors; Isoxazoles; Lipoxygenase Inhibitors; Metalloendopeptidases; Oxazolidinones; Oximes; Phospholipase A2 Inhibitors; Probucol; Pyrimidines; Quinolines; Thiophenes