Beneficial effects of the micronized purified flavonoid fraction (MPFF, Daflon® 500 mg) on microvascular damage elicited by sclerotherapy.

Objectives: To evaluate if the micronized purified flavonoid fraction (MPFF) treatment could reduce the side effects of sclerotherapy (a procedure frequently used to treat venous disease manifestations) by minimizing the inflammatory response within the surrounding tissues.

Method: Twenty-two male New Zealand rabbits were treated by gavage with micronized purified flavonoid fraction (MPFF; 300 mg/kg/day) or vehicle (10% lactose solution) during 21 consecutive days, starting 7 days before sclerotherapy. The sclerotherapy consisted of an injection containing 5% ethanolamine oleate solution in the rabbit's dorsal ear vein.

Preserved regulation of renal perfusion pressure by small and intermediate conductance KCa channels in hypertensive mice with or without renal failure.

The purpose of this study was to assess, in the murine kidney, the mechanisms underlying the endothelium-dependent control of vascular tone and whether or not, in a severe model of hypertension and renal failure, KCa channels contribute to its regulation. Wild-type (BL) and double-transgenic female mice expressing human angiotensinogen and renin (AR) genes received either control or a high-salt diet associated to a nitric oxide (NO) synthase inhibitor treatment (BLSL and ARSL). Changes in renal perfusion pressure (RPP) were measured in isolated perfused kidneys.

Mechanisms of the vasorelaxing effects of CORM-3, a water-soluble carbon monoxide-releasing molecule: interactions with eNOS.

The purpose of the present work was to elucidate the mechanisms underlying the endothelium-dependent and endothelium-independent components of the vascular relaxation induced by a water-soluble and ruthenium-based carbon monoxide (CO)-releasing agent, tricarbonylchloro(glycinato)ruthenium(II) (CORM-3). Changes in isometric tension and cyclic guanosine monophosphate (cGMP) production were measured in isolated aortic rings from normotensive Wistar-Kyoto rats. Nitric oxide (NO) generation was assessed in cultured human umbilical vein endothelial cells (HUVEC) by electron spin resonance.

KCa 3.1 channels maintain endothelium-dependent vasodilatation in isolated perfused kidneys of spontaneously hypertensive rats after chronic inhibition of NOS.

Background And Purpose: The purpose of the study was to investigate renal endothelium-dependent vasodilatation in a model of severe hypertension associated with kidney injury.

Experimental Approach: Changes in perfusion pressure were measured in isolated, perfused kidneys taken from 18-week-old Wistar-Kyoto rat (WKY), spontaneously hypertensive rats (SHR) and SHR treated for 2 weeks with N(ω) -nitro-L-arginine methyl ester in the drinking water (L-NAME-treated SHR, 6 mg·kg(-1) ·day(-1) ).

Key Results: Acetylcholine caused similar dose-dependent renal dilatation in the three groups.

Chronic reduction of nitric oxide level in adult spontaneously hypertensive rats induces aortic stiffness similar to old spontaneously hypertensive rats.

Introduction: Age and hypertension are two major determinants of arterial stiffness, as well as endothelial dysfunction. The present study was designed to test whether a chronic reduction of endogenous nitric oxide (NO) produces arterial stiffening close to that observed in old spontaneously hypertensive rats (SHR), and also to study the effect of an acute or a chronic decrease in blood pressure (BP) on aortic distensibility.

Methods: BP, aortic stiffness, endothelial dysfunction and remodelling were measured in male adult (20-week-old) SHR, in adult SHR treated with a nonspecific NO synthase inhibitor L-NAME (SHR/L-NAME) for 2 weeks, in adult SHR/L-NAME cotreated with perindopril (1 mg/kg/day) and in old SHR (55-week-old).

Activation of thromboxane receptor modulates interleukin-1β-induced monocyte adhesion--a novel role of Nox1.

Activation of thromboxane receptors (TPr) may promote atherosclerosis by enhancing oxidative stress and inflammation. This study examined the role of Nox1, an NADPH-oxidase subunit, in the enhancement of interleukin (IL)-1β-induced monocyte adhesion by TPr. In cultured rat aortic vascular smooth muscle cells (VSMCs), U46619, a stable thromboxane A(2) mimetic, together with interleukin-1β significantly enhanced Nox1 mRNA expression, as well as adhesion of THP-1 monocytes.

The polyphenols resveratrol and S17834 prevent the structural and functional sequelae of diet-induced metabolic heart disease in mice.

Background: Diet-induced obesity is associated with metabolic heart disease characterized by left ventricular hypertrophy and diastolic dysfunction. Polyphenols such as resveratrol and the synthetic flavonoid derivative S17834 exert beneficial systemic and cardiovascular effects in a variety of settings including diabetes mellitus and chronic hemodynamic overload.

Methods And Results: We characterized the structural and functional features of a mouse model of diet-induced metabolic syndrome and used the model to test the hypothesis that the polyphenols prevent myocardial hypertrophy and diastolic dysfunction.

High-fat diet increases and the polyphenol, S17834, decreases acetylation of the sirtuin-1-dependent lysine-382 on p53 and apoptotic signaling in atherosclerotic lesion-prone aortic endothelium of normal mice.

Our purpose was to determine if high-fat diet and treatment with a polyphenol regulate the acetylation of lysine-382 of p53, the site regulated by sirtuin-1, and apoptosis in the endothelium of the atherosclerotic lesion-prone mouse aortic arch. In cultured endothelial cells, 2 atherogenic stimuli, hydrogen peroxide and tumor necrosis factor-α, increased the acetylation of p53 lysine-382, and caspase-3 cleavage, an indicator of apoptotic signaling. The polyphenol, S17834, significantly prevented these changes.

Aortic stiffness in vivo in hypertensive rat via echo-tracking: analysis of the pulsatile distension waveform.

Large-artery stiffening is a major risk factor in aging and hypertension. Elevated blood pressure (BP) and vascular wall properties participate in arterial stiffening; we aimed to evaluate their respective role by combining echo-tracking and the spontaneously hypertensive rats (SHR) treated with low doses of a nitric oxide synthase inhibitor, shown to have arterial stiffening. Normotensive [Wistar-Kyoto (WKY)], SHR, and SHR treated for 2 wk with N(G)-nitro-L-arginine methyl ester (SHRLN) were anesthetized; BP and distension (pulsatile displacement) of the aortic walls with the ArtLab echo-tracking device were measured.

AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice.

AMPK has emerged as a critical mechanism for salutary effects of polyphenols on lipid metabolic disorders in type 1 and type 2 diabetes. Here we demonstrate that AMPK interacts with and directly phosphorylates sterol regulatory element binding proteins (SREBP-1c and -2). Ser372 phosphorylation of SREBP-1c by AMPK is necessary for inhibition of proteolytic processing and transcriptional activity of SREBP-1c in response to polyphenols and metformin.

(Pro)renin promotes fibrosis gene expression in HEK cells through a Nox4-dependent mechanism.

The (pro)renin receptor (PRR) has recently been demonstrated to bind equally well renin and its precursor, prorenin, leading to a similar intracellular signaling independent of angiotensin II. In this study, we report that human embryonic kidney cells (HEK) exposed to renin or prorenin for 24 h in the presence of a blocking concentration of the angtiotensin-converting enzyme inhibitor perindoprilate increased superoxide anion production as measured by luminescence (lucigenin) and electron spin resonance spectroscopy (hydroxylamine radical transition). Also, both renin and prorenin increased Nox4 expression while Nox2, p47(phox), and p67(phox) remained unchanged.

TP receptors and oxidative stress hand in hand from endothelial dysfunction to atherosclerosis.

Thromboxane A(2) and the activation of TP receptors that it causes play an important role in platelet aggregation and therefore in thrombosis. However, TP receptors are also involved in the pathologies of the vascular wall including impaired endothelium-dependent vasodilation, increased oxidant generation, and increased expression of adhesion molecules. The beneficial effects of TP antagonists on the vascular wall attenuate these features of vascular disease.

The anti-aggregating effect of BAY 41-2272, a stimulator of soluble guanylyl cyclase, requires the presence of nitric oxide.

Background And Purpose: The purpose of the present study was to determine whether a stimulator of soluble guanylyl cyclase, BAY 41-2272, inhibits platelet aggregation and to clarify its interaction with nitric oxide (NO).

Experimental Approach: Blood was collected from anaesthetized Wistar Kyoto rats. The aggregation of washed platelets was measured and the production of cAMP and cGMP was determined.

Anti-aggregating effect of BAY 58-2667, an activator of soluble guanylyl cyclase.

The purpose of the present study was to determine whether an activator of soluble guanylyl cyclase (sGC), BAY 58-2667, inhibits platelet aggregation and to clarify its mechanism of action. Blood was collected from anesthetized WKY rats. The aggregation of washed platelet was measured and the production of cAMP and cGMP was determined.

The thromboxane/endoperoxide receptor (TP): the common villain.

The stimulation of thromboxane/endoperoxide receptors (TP) elicits diverse physiological/pathophysiological reactions, including platelet aggregation and contraction of vascular smooth muscle. Furthermore, the activation of endothelial TP promotes the expression of adhesion molecules and favors adhesion and infiltration of monocytes/macrophages. In various cardiovascular diseases, endothelial dysfunction is predominantly the result of the release of endothelium-derived contracting factors that counteract the vasodilator effect of nitric oxide produced by the endothelial nitric oxide synthase.

Role of thromboxane TP and angiotensin AT1 receptors in lipopolysaccharide-induced arterial dysfunction in the rabbit: an in vivo study.

Inflammation plays a major role in pathological conditions leading to cardiovascular events. Administration of lipopolysaccharide to animals decreases arterial blood flow, in contrast to the dilatations that occur in microvessels. The purpose of the present study was to determine whether or not lipopolysaccharide, in vivo, evokes arterial constriction and if so the underlying mechanisms.

Nox4 mediates the expression of plasminogen activator inhibitor-1 via p38 MAPK pathway in cultured human endothelial cells.

Introduction: Plasminogen Activator Inhibitor-1 (PAI-1) is the most potent endogenous inhibitor of fibrinolysis which is implicated in the pathogenesis of myocardial infarction and metabolic syndrome. The formation of reactive oxygen species (ROS) plays an important role in the pathology of vascular disorders and has been shown to increase PAI-1 expression by endothelial cells. Growing evidence indicates that NADPH oxidase and in particular the constitutively active Nox4-p22(phox) complexes are major sources of ROS in endothelial cells.

Design, synthesis, and biological evaluation of 1,5-benzothiazepine-4-one derivatives targeting factor VIIa/tissue factor.

The 1,5-benzothiazepine-4-one scaffold was earlier shown to provide efficient protease inhibitors. In this contribution, we describe its use in the design of factor VIIa/tissue factor inhibitors. A series containing a scaffold non-substituted on its aryl part led to compound 20 with an IC(50) of 2.

Endothelium-dependent contractions in SHR: a tale of prostanoid TP and IP receptors.

In the aorta of spontaneously hypertensive rats (SHR), the endothelial dysfunction is due to the release of endothelium-derived contracting factors (EDCFs) that counteract the vasodilator effect of nitric oxide, with no or minor alteration of its production. The endothelium-dependent contractions elicited by acetylcholine (ACh) involve an increase in endothelial [Ca(2+)](i), the production of reactive oxygen species, the activation of endothelial cyclooxygenase-1, the diffusion of EDCF and the subsequent stimulation of smooth muscle cell TP receptors. The EDCFs released by ACh have been identified as PGH(2) and paradoxically prostacyclin.

Aging and prostacyclin responses in aorta and platelets from WKY and SHR rats.

In spontaneously hypertensive rat (SHR) aorta, prostacyclin is an endothelium-derived contracting factor contributing to the endothelial dysfunction. This study was designed to determine whether the impairment of the prostacyclin response is influenced by aging and whether such a dysfunction is observed in platelets. Isometric tension was measured in aortic rings, and aggregation was studied in platelet-rich plasma taken from 3-, 6-, and 15-mo-old Wistar-Kyoto rats (WKY) and SHR.

Carbon monoxide induces relaxation of human internal thoracic and radial arterial grafts.

Carbon monoxide is produced by the degradation of heme by intracellular heme-oxygenase. The aim of our study was to evaluate, in vitro, the vasodilating effect of carbon monoxide and its mechanisms of action on human internal thoracic and radial artery grafts. Segments of human internal thoracic artery and radial artery, obtained from isolated coronary artery bypass surgery patients, were studied in organ chambers.

Altered thrombus formation in von Willebrand factor-deficient mice expressing von Willebrand factor variants with defective binding to collagen or GPIIbIIIa.

The role of von Willebrand factor (VWF) in thrombosis involves its binding to a number of ligands. To investigate the relative importance of these particular interactions in the thrombosis process, we have introduced mutations into murine VWF (mVWF) cDNA inhibiting VWF binding to glycoprotein (Gp) Ib, GPIIbIIIa, or to fibrillar collagen. These VWF mutants were expressed in VWF-deficient mice (VWF(-/-)) by using an hydrodynamic injection approach, and the mice were studied in the ferric chloride-induced injury model.

SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase.

Resveratrol may protect against metabolic disease through activating SIRT1 deacetylase. Because we have recently defined AMPK activation as a key mechanism for the beneficial effects of polyphenols on hepatic lipid accumulation, hyperlipidemia, and atherosclerosis in type 1 diabetic mice, we hypothesize that polyphenol-activated SIRT1 acts upstream of AMPK signaling and hepatocellular lipid metabolism. Here we show that polyphenols, including resveratrol and the synthetic polyphenol S17834, increase SIRT1 deacetylase activity, LKB1 phosphorylation at Ser(428), and AMPK activity.

Distinct role of nox1, nox2, and p47phox in unstimulated versus angiotensin II-induced NADPH oxidase activity in human venous smooth muscle cells.

Human saphenous veins (SV) are used for coronary bypass surgery despite the higher rate of graft failure observed as compared to arteries. A higher production of reactive oxygen species (ROS) in SV than in internal mammary artery (IMA) has been incriminated as possibly implicated in graft failure. NADPH oxidase, involved in vascular ROS production, was therefore characterized in human smooth muscle cells from SV.