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2.
Pharmacol Res ; 66(5): 409-18, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22902525

ABSTRACT

To investigate the vasorelaxant efficacy of nitrite and nitroxyl (HNO) in porcine coronary (micro)arteries (PC(M)As), evaluating their role as endothelium-derived hyperpolarizing factors (EDHFs), preconstricted PCAs and PCMAs were exposed to UV light (a well-known inductor of nitrite; wave-length: 350-370nm), nitrite, the HNO donor Angeli's salt, or bradykinin. UV light-induced relaxation of PCAs increased identically after endothelium removal and endothelial nitric oxide (NO) synthase (eNOS) blockade. UV light-induced relaxation diminished during Na(+)-K(+)-ATPase inhibition and S-nitrosothiol-depletion, and disappeared during NO scavenging with hydroxocobalamin or soluble guanylyl cyclase (sGC) inhibition with ODQ. Nitrite-induced relaxation of PCAs required millimolar levels, i.e., >1000 times endogenous vascular nitrite. Angeli's salt relaxed PCMAs more potently than PCAs, and this was due to the fact that HNO directly activated sGC in PCMAs, whereas in PCAs this occurred following its conversion to NO only. sGC activation by NO/HNO resulted in Na(+)-K(+)-ATPase stimulation and K(v) channel activation. The HNO scavenger l-cysteine blocked bradykinin-induced relaxation in PCAs, and potentiated it in PCMAs. The latter did not occur in the presence of hydroxocobalamin, suggesting that it depended on l-cysteine-induced generation of vasorelaxant S-nitrosothiols. In all experimental setups, incubation with red wine extract mimicked the effects of ODQ. In conclusion, nitrite, via its conversion to NO and S-nitrosothiols, and HNO, either directly, or via its conversion to NO, mediate relaxant effects involving the sGC-cGMP pathway, Na(+)-K(+)-ATPase and/or K(v) channels. Red wine extract counteracts these beneficial effects. NO blocks nitrite activation, and HNO, but not nitrite, may act as EDHF in the coronary vascular bed.


Subject(s)
Coronary Vessels/physiology , Nitrites/pharmacology , Nitrogen Oxides/pharmacology , Vasodilation/physiology , Animals , Biological Factors/physiology , Coronary Vessels/drug effects , Coronary Vessels/radiation effects , Cyclic GMP/physiology , Guanylate Cyclase/physiology , Receptors, Cytoplasmic and Nuclear/physiology , Sodium-Potassium-Exchanging ATPase/physiology , Soluble Guanylyl Cyclase , Swine , Ultraviolet Rays , Vasodilation/drug effects , Vasodilation/radiation effects , Wine
3.
Clin Sci (Lond) ; 123(8): 499-507, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22563892

ABSTRACT

Red wine polyphenols may preserve endothelial function during aging. Endothelial cell senescence enhances age-related endothelial dysfunction. We investigated whether RWE (red wine extract) prevents oxidative-stress-induced senescence in HUVECs (human umbilical-vein endothelial cells). Senescence was induced by exposing HUVECs to tBHP (t-butylhydroperoxide), and quantified by senescence-associated ß-galactosidase staining. RWE (0-50 µg/ml) concentration dependently decreased senescence by maximally 33±7.1%. RWE prevented the senescence-associated increase in p21 protein expression, inhibited tBHP-induced DNA damage of endothelial cells and induced relaxation of PCAs (porcine coronary arteries). Inhibition of SIRT1 (sirtuin 1) by sirtinol partially reversed the effect of RWE on tBHP-induced senescence, whereas both the NOS (nitric oxide synthase) inhibitor L-NMMA (NG-monomethyl-L-arginine) and the COX (cyclo-oxygenase) inhibitor indomethacin fully inhibited it. Furthermore, incubation of HUVECs with RWE increased eNOS (endothelial NOS) and COX-2 mRNA levels as well as phosphorylation of eNOS at Ser1177. RWE protects endothelial cells from tBHP-induced senescence. NO and COX-2, in addition to activation of SIRT1, play a critical role in the inhibition of senescence induction in human endothelial cells by RWE.


Subject(s)
Cellular Senescence/drug effects , Human Umbilical Vein Endothelial Cells/drug effects , Oxidative Stress/drug effects , Wine/analysis , Antioxidants/pharmacology , Cells, Cultured , Cellular Senescence/physiology , DNA Damage/drug effects , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Human Umbilical Vein Endothelial Cells/cytology , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Nitric Oxide Synthase Type III/metabolism , Oxidative Stress/physiology , Plant Extracts/pharmacology , Polyphenols/pharmacology , Prostaglandins/metabolism , Resveratrol , Sirtuin 1/physiology , Stilbenes/pharmacology , beta-Galactosidase/metabolism , tert-Butylhydroperoxide/pharmacology
4.
Am J Hypertens ; 25(6): 718-23, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22421906

ABSTRACT

BACKGROUND: Epidemiological data suggest that modest red wine consumption may reduce cardiovascular disease risk. Red wine polyphenols improved human endothelial vascular function and reduced blood pressure (BP) in animal studies, but the results of human intervention studies investigating the effect of red wine polyphenols on BP are inconsistent. The objective was to investigate whether polyphenols extracted from red wine reduce peripheral and central BP in subjects with high-normal BP or grade 1 hypertension. METHODS: In a double-blind, placebo-controlled three-period crossover trial, we assigned 61 subjects (mean age 61.4 ± 8.4 years) with office systolic BP 135 ± 9 mm Hg and diastolic BP 82 ± 8 mm Hg to dairy drinks containing either placebo, 280 mg red wine polyphenols, or 560 mg red wine polyphenols. After each 4-week intervention period, office and 24-h ambulatory BP measurements, and central hemodynamic measurements derived from continuous finger BP recordings were assessed. RESULTS: Polyphenol treatment did not significantly affect 24-h BP: systolic/diastolic BP was 143 ± 2/84 ± 1 mm Hg after placebo, 143 ± 2/84 ± 1 mm Hg after 280 mg/day of red wine polyphenols, and 142 ± 2/83 ± 1 mm Hg after 560 mg/day. Neither dose of polyphenol treatment changed office or central BP, aortic augmentation index (AIx) or pulse wave reflection index. CONCLUSIONS: Intake of red wine polyphenols in two different dosages for 4 weeks did not decrease peripheral or central BP in subjects with a high normal or grade 1 hypertension. Our findings do not support the hypothesis that polyphenols account for the suggested cardiovascular benefits of red wine consumption by lowering BP.


Subject(s)
Blood Pressure/drug effects , Blood Pressure/physiology , Hypertension/physiopathology , Polyphenols/pharmacology , Wine , Adult , Aged , Blood Glucose/metabolism , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/prevention & control , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Female , Hemodynamics/drug effects , Hemodynamics/physiology , Humans , Lipids/blood , Male , Middle Aged , Risk Factors , Severity of Illness Index
5.
Diabetes Care ; 35(2): 424-6, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22228742

ABSTRACT

OBJECTIVE: To investigate whether SIRT1, a nutrient-sensing histone deacetylase, influences fetal programming during malnutrition. RESEARCH DESIGN AND METHODS: In 793 individuals of the Dutch Famine Birth Cohort, we analyzed the interaction between three SIRT1 single nucleotide polymorphisms (SNPs) and prenatal exposure to famine on type 2 diabetes risk. RESULTS: In the total population (exposed and unexposed), SIRT1 variants were not associated with type 2 diabetes. A significant interaction was found between two SIRT1 SNPs and exposure to famine in utero on type 2 diabetes risk (P = 0.03 for rs7895833; P = 0.01 for rs1467568). Minor alleles of these SNPs were associated with a lower prevalence of type 2 diabetes only in individuals who had been exposed to famine prenatally (odds ratio for rs7895833 0.50 [95% CI 0.24-1.03], P = 0.06; for rs1467568 0.48 [0.25-0.91], P = 0.02). CONCLUSIONS: SIRT1 may be an important genetic factor involved in fetal programming during malnutrition, influencing type 2 diabetes risk later in life.


Subject(s)
Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/genetics , Malnutrition/genetics , Polymorphism, Single Nucleotide/genetics , Sirtuin 1/genetics , Female , Genotype , Humans , Pregnancy , Prenatal Exposure Delayed Effects/genetics
6.
Atherosclerosis ; 219(2): 690-3, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21925660

ABSTRACT

OBJECTIVE: Fetal exposure to maternal hypercholesterolemia increases the extent of fatty-streak formation in fetal aortas as well as the rate of progression, and may therefore increase coronary heart disease (CHD) risk later in life. We hypothesized that the risk of CHD in untreated individuals with familial hypercholesterolemia (FH) is more extreme when the disease is transmitted maternally. METHODS: In a large Dutch pedigree carrying the V408M mutation in the low-density lipoprotein (LDL) receptor gene, 161 individuals over seven generations were identified for which FH status and parent of origin of FH were known. We calculated standardized mortality ratios (SMR) and compared the consequences of maternal and paternal inheritance of FH by Poisson regression analysis. RESULTS: Maternally inherited FH was associated with significantly higher excess mortality than FH transmitted by fathers (relative risk 2.2; p = 0.048): the SMR of maternal inheritance was 2.49 (95% confidence interval (CI) 1.45-3.99; p = 0.001), whereas it was not significantly increased in paternally inherited FH (SMR 1.30, 95% CI 0.65-2.32; p = 0.234). CONCLUSION: Mortality rates are more increased when FH is inherited through the mother, supporting the fetal origin of adulthood disease hypothesis with all cause death, the most indisputable outcome measure. Future research should explore safe options for cholesterol-lowering therapy of pregnant women with FH in order to prevent unfavourable (epigenetic) consequences leading to atherosclerosis in their children.


Subject(s)
Hyperlipoproteinemia Type II/genetics , Hyperlipoproteinemia Type II/mortality , Mothers , Mutation , Receptors, LDL/genetics , Fathers , Female , Genetic Predisposition to Disease , Heredity , Humans , Male , Netherlands , Pedigree , Phenotype , Risk Assessment , Risk Factors
7.
Am J Hypertens ; 24(2): 162-8, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21088673

ABSTRACT

BACKGROUND: Polyphenols in red wine are supposed to improve endothelial function. We investigated whether daily red wine consumption improves in-vivo vascular function by reducing endothelin-1 (ET-1). Additional pathways mediating this effect were studied using porcine coronary arteries (PCAs). METHODS: Eighteen young healthy women drank red wine daily for 3 weeks. Vascular function was evaluated by determining forearm blood flow (FBF) responses to endothelium-dependent (acetylcholine (ACh)) and endothelium-independent (sodium nitroprusside (SNP)) vasodilators. PCAs were suspended in organ baths and exposed to the endothelium-dependent vasodilator bradykinin, the nitric oxide (NO) donor S-nitroso-N-acetyl-L,L-penicillamine (SNAP) and/or red wine extract (RWE). RESULTS: ACh-induced and SNP-induced FBF increases were equally enhanced after 3 weeks of red wine consumption, but an immediate enhancement (i.e., after drinking the first glass) was not observed. Vice versa, plasma ET-1 levels were not decreased after 3 weeks, but we observed an acute drop after drinking one glass of wine. RWE relaxed preconstricted PCAs in an endothelium-, NO-, and soluble guanylyl cyclase (sGC)/guanosine-3',5'-cyclic monophosphate (cGMP)-dependent manner. Short RWE exposure reduced the response to bradykinin and SNAP by inactivating sGC. This effect disappeared upon prolonged RWE exposure. CONCLUSIONS: The enhanced FBF response following 3 weeks of red wine consumption, but not after one glass, reflects a change in smooth muscle sensitivity. Alterations in sGC responsiveness/activity, rather than changes in ET-1, appear to underlie this phenomenon.


Subject(s)
Alcohol Drinking , Forearm/blood supply , Guanylate Cyclase/metabolism , Muscle, Smooth, Vascular/drug effects , Receptors, Cytoplasmic and Nuclear/metabolism , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Wine , Adult , Animals , Biomarkers/blood , Cells, Cultured , Coronary Vessels/drug effects , Coronary Vessels/enzymology , Dose-Response Relationship, Drug , Endothelial Cells/drug effects , Endothelial Cells/enzymology , Endothelin-1/blood , Female , Humans , In Vitro Techniques , Muscle, Smooth, Vascular/enzymology , Nitric Oxide/metabolism , Perfusion , Plethysmography , Regional Blood Flow/drug effects , Signal Transduction/drug effects , Soluble Guanylyl Cyclase , Swine , Time Factors , Young Adult
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