benzofurans and Vascular-Diseases

This study investigated the roles of bone morphogenetic protein-4 (BMP4) and ROS in diabetic endothelial dysfunction and explored whether Salvianolic acid B (Sal B) improved endothelial function by affecting BMP4-ROS in diabetic mice.. db/db mice were orally administrated with Sal B (10 mg/kg/day) for one week while db/m + mice were injected with adenoviral vectors delivering BMP4 (3 × 10. We first revealed the existence of a BMP4-ROS cycle in db/db mice, which stimulated p38 MAPK/JNK/caspase 3 and thus participated in endothelial dysfunction. One week-treatment or 24 h-incubation with Sal B disrupted the cycle, suppressed p38 MAPK/JNK/caspase 3 cascade, and improved endothelium-dependent relaxations (EDRs) in db/db mouse aortas. Importantly, in vivo Sal B treatment also improved flow-mediated dilatation in db/db mouse second order mesenteric arteries. Furthermore, in vivo BMP4 overexpression induced oxidative stress, stimulated p38 MAPK/JNK/caspase 3, and impaired EDRs in db/m + mouse aortas, which were all reversed by Sal B.. The present study demonstrates that Sal B ameliorates endothelial dysfunction through breaking the BMP4-ROS cycle and subsequently inhibiting p38 MAPK/JNK/caspase 3 in diabetic mice and provides evidence for the additional new mechanism underlying the benefit of Sal B against diabetic vasculopathy.

Topics: Animals; Aorta; Benzofurans; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins; Caspase 3; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Male; MAP Kinase Signaling System; Mesenteric Arteries; Mice; Mice, Inbred C57BL; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Reactive Oxygen Species; Vascular Diseases; Vasodilation

Salvia miltiorrhiza (Danshen), a traditional Chinese herbal medicine, is commonly used for the prevention and treatment of cardiovascular disorders including atherosclerosis. However, the mechanisms responsible for the vasoprotective effects of Danshen remain largely unknown. Salvianolic acid B (Sal B) represents one of the most bioactive compounds that can be extracted from the water-soluble fraction of Danshen. We investigated the effects of Danshen and Sal B on the inflammatory response in murine macrophages. Danshen and Sal B both induced the expression of heme oxygenase-1 (HO-1) and inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-activated RAW 264.7 cells. Inhibition of HO activity using Sn-protoporphyrin-IX (SnPP) abolished the inhibitory effect of Sal B on NO production and iNOS expression. Sal B increased macrophage arginase activity in a dose-dependent manner and diminished LPS-inducible tumor necrosis factor-α production. These effects were also reversed by SnPP. These data suggest that HO-1 expression plays an intermediary role in the anti-inflammatory effects of Sal B. In contrast to the observations in macrophages, Sal B dose-dependently inhibited arginase activity in murine liver, kidney, and vascular tissue. Furthermore, Sal B increased NO production in isolated mouse aortas through the inhibition of arginase activity and reduction of reactive oxygen species production. We conclude that Sal B improves vascular function by inhibiting inflammatory responses and promoting endothelium-dependent vasodilation. Taken together, we suggest that Sal B may represent a potent candidate therapeutic for the treatment of cardiovascular diseases associated with endothelial dysfunction.

Topics: Animals; Arginase; Benzofurans; Blotting, Western; Drugs, Chinese Herbal; Electrophoretic Mobility Shift Assay; Fibrinolytic Agents; Heme Oxygenase-1; Humans; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase Type II; Phenanthrolines; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Salvia miltiorrhiza; Tumor Necrosis Factor-alpha; Vascular Diseases

Atherosclerosis and restenosis are inflammatory responses involving free radicals and lipid peroxidation and may be prevented/cured by antioxidant-mediated lipid peroxidation inhibition. Salvianolic acid (Sal B), a water-soluble antioxidant obtained from a Chinese medicinal herb, is believed to have multiple preventive and therapeutic effects against human vascular diseases. In this study the in vitro and in vivo inhibitory effects of Sal B on oxidative stress were determined.. In human aortic endothelial cells (HAECs), Sal B reduced oxidative stress, inhibited low-density lipoprotein (LDL) oxidation and reduced oxidised LDL-induced cytotoxicity. Sal B inhibited Cu(2+) -induced LDL oxidation in vitro (with a potency 16.3 times that of probucol) and attenuated HAEC-mediated LDL oxidation as well as reactive oxygen species (ROS) production. In cholesterol-fed New Zealand White rabbits (with probucol as positive control), Sal B intake reduced Cu(2+) -induced LDL oxidation, lipid deposition in the thoracic aorta, intimal thickness of the aortic arch and thoracic aorta and neointimal formation in the abdominal aorta.. The data obtained in this study suggest that Sal B protects HAECs from oxidative injury-mediated cell death via inhibition of ROS production. The antioxidant activity of Sal B may help explain its efficacy in the treatment of vascular diseases.

Topics: Animals; Antioxidants; Aorta; Benzofurans; Cholesterol, Dietary; Copper; Drugs, Chinese Herbal; Endothelial Cells; Humans; Hypercholesterolemia; Hyperplasia; Lipid Metabolism; Lipid Peroxidation; Lipoproteins, LDL; Oxidative Stress; Phytotherapy; Rabbits; Reactive Oxygen Species; Salvia miltiorrhiza; Tunica Intima; Vascular Diseases

Hyperuricemia is associated with hypertension and vascular disease, but whether this represents a causal relationship or an epiphenomenon remains unknown. We recently reported a model of mild hyperuricemia in rats that results in increased blood pressure and mild renal fibrosis. In this study, we examined the effect of hyperuricemia on the renal vasculature. Rats fed 2% oxonic acid and a low-salt diet for 7 wk developed mild hyperuricemia (1.8 vs. 1.4 mg/dl, P < 0.05), hypertension [147 vs. 127 mmHg systolic blood pressure (SBP), P < 0.05], and afferent arteriolar thickening, with a 35% increase in medial area (P < 0.05). Allopurinol or benziodarone prevented the hyperuricemia, hypertension, and arteriolopathy. Hydrochlorothiazide treatment did not prevent the hyperuricemia or arteriolopathy despite controlling blood pressure. In contrast, the arteriolopathy and hypertension were prevented by both enalapril and losartan. Uric acid also directly stimulated vascular smooth muscle cell proliferation in vitro, and this was partially inhibited by losartan. Thus hyperuricemia induces a renal arteriolopathy in rats that is blood pressure independent and involves the renin-angiotensin system.

Topics: Administration, Oral; Allopurinol; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Arterioles; Benzofurans; Blood Pressure; Diuretics; Enalapril; Hydrochlorothiazide; Hypertension; Kidney; Losartan; Male; Muscle, Smooth, Vascular; Oxonic Acid; Rats; Rats, Sprague-Dawley; Sodium Chloride Symporter Inhibitors; Sodium Chloride, Dietary; Uric Acid; Uricosuric Agents; Vascular Diseases

Topics: Aspartic Acid Endopeptidases; Benzazepines; Benzhydryl Compounds; Benzofurans; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Enzyme Inhibitors; Heart Failure; Humans; Metalloendopeptidases; Organophosphonates; Pyrimidines; Vascular Diseases; Vasoconstrictor Agents

Topics: Aged; Arteriosclerosis; Benzofurans; Female; Humans; Male; Middle Aged; Retinal Degeneration; Retinal Diseases; Retinitis; Sclerosis; Vascular Diseases; Vasodilator Agents

Topics: Benzofurans; Flavonoids; Humans; Leg; Phlebitis; Phytotherapy; Plants, Medicinal; Rutin; Thrombophlebitis; Varicose Veins; Vascular Diseases; Veins

Topics: Acetylcholine; Animals; Anti-Inflammatory Agents; Benzofurans; Blood Coagulation; Bradykinin; Capillary Permeability; Capillary Resistance; Chronic Disease; Depression, Chemical; Dogs; Edema; Epinephrine; Female; Fibrinolysis; Fibrinolytic Agents; Guinea Pigs; Histamine H1 Antagonists; Mycobacterium Infections; Norepinephrine; Rabbits; Rats; Serotonin Antagonists; Stimulation, Chemical; Vascular Diseases

Topics: Angina Pectoris; Benzofurans; Drug Therapy; Furans; Hypothyroidism; Intermittent Claudication; Iodides; Iodine; Toxicology; Vascular Diseases; Vasodilator Agents