Effects of nebivolol in obese African Americans with hypertension (NOAAH): markers of inflammation and obesity in response to exercise-induced stress.

We sought to determine whether the antihypertensive drug nebivolol has beneficial effects on vascular markers of inflammation and oxidation in obese African-American patients with hypertension when exposed to exercise-induced stress. Forty-three obese, African-American subjects with hypertension were treated with nebivolol (5-10 mg/day) for 8 weeks. Before treatment the subjects underwent an exercise treadmill study to a level of eight metabolic equivalents. Circulating levels of soluble interleukin-6 (sIL-6), vascular cell adhesion molecule (VCAM-1), adiponectin and leptin were measured at pre-treadmill, and 1 min, 30 min, 60 min and 24 h after treadmill. After the 8-week treatment period, exercise treadmill study and the measurement of markers were repeated. Treatment with nebivolol reduced levels of sVCAM-1 at pre-exercise by 21% and at 1 and 30 min by 12.5 and 20%, respectively (P<0.005 from corresponding time point). In nebivolol-treated patients there was a reduction in sIL-6 levels by 20% and pre-exercise and at 1 and 60 min by 19.7 and 33.5%, respectively (P<0.005 from corresponding time point). Treatment with nebivolol increased levels of serum adiponectin by 28% (P=0.012) and decreased levels of leptin by 32% (P<0.005 from pre-treatment). Treatment with nebivolol improves markers of inflammation and obesity in a high-risk African-American population. Moreover, this effect is potentiated in response to exercise-induced stress. These results suggest that nebivolol differentially regulates markers of inflammation and obesity, thereby providing vascular protection.

Antihypertensive drug therapy and blood pressure control in men and women: an international perspective.

Cardiovascular death represents the single largest cause of mortality in women with 70% of deaths attributable to modifiable risk factors, such as hypertension. This analysis aims at evaluating, whether there are gender disparities in antihypertensive drug usage and blood pressure (BP) control. We included 18 017 patients with arterial hypertension from the International Survey Evaluating Microalbuminuria Routinely by Cardiologists in patients with Hypertension (I-SEARCH). The study was conducted between September 2005 and March 2006 in 26 countries, and data on patient demographics, cardiovascular disease and risk factors, BP, and cardiovascular drug treatment were collected. Mean systolic blood pressure (SBP) was 2.1 mm Hg higher in women (150.6+/-0.35 mm Hg, n=8357/18 017) than in men (148.5+/-0.35 mm Hg; P<0.0001, n=9526/18 017), whereas no difference in diastolic BP was seen (88.2+/-0.20 vs 88+/-0.20 mm Hg; P=0.198). Gender differences in SBP were more pronounced in diabetic as compared with non-diabetic patients (3.5 vs 1.7 mm Hg, n=4272 vs n=13 611; P<0.0001) and became evident at an age 55 years old. Overall BP-control rate was 33.6% in men and 30.6% in women (P<0.0001) and was lower in diabetic as compared with non-diabetic patients. In all, 30% of patients used one, 40% used two and 30% used > or = 3 drugs without gender differences. Response rates to different drug regimens appeared to be similar. However, women received more frequently thiazides and beta-blockers, and less frequently ACE-inhibitors as monotherapy. Major efforts are required to improve BP-management, especially in women.

The effects of extended-release niacin on carotid intimal media thickness, endothelial function and inflammatory markers in patients with the metabolic syndrome.

BACKGROUND: Niacin is an agent that significantly increases high-density lipoprotein cholesterol (HDL-C), but its effects on surrogate markers of atherosclerosis and inflammatory markers are less clear. We studied the effects of niacin on carotid intimal media thickness (IMT), brachial artery reactivity as well as markers of inflammation and the metabolic profile of patients with metabolic syndrome. METHODS AND RESULTS: Fifty patients with the metabolic syndrome (Adult Treatment Panel (ATP) III criteria) were randomised to either extended-release niacin (1000 mg/day) or placebo. After 52 weeks of treatment, there was a change of carotid IMT of +0.009 +/- 0.003 mm in the placebo group and -0.005 +/- 0.002 mm in the niacin group (p = 0.021 between groups). Endothelial function improved by 22% in the group treated with niacin (p < 0.001), whereas no significant changes were seen in the placebo group. High sensitivity C-reactive protein decreased by 20% in the group treated with niacin for 52 weeks (p = 0.013). Niacin increased HDL-C (p < 0.001) and decreased low-density lipoprotein cholesterol and triglycerides (p < 0.001) significantly, and there were no adverse effects on fasting glucose levels after 52 weeks of treatment. CONCLUSION: Extended-release niacin therapy effects a regression in carotid intimal medial thickness and improvement in metabolic parameters (increased HDL and reduced triglycerides). Furthermore, extended-release niacin may demonstrate an anti-atherogenic effect in the metabolic syndrome by improving endothelial function and decreasing vascular inflammation.

The potential role of antiplatelet agents in modulating inflammatory markers in atherothrombosis.

Atherothrombosis is the process that links atherosclerotic lesion development with unpredictable and life-threatening ischemic vascular events such as angina, myocardial infarction, transient ischemic attack, and stroke. Atherothrombosis is triggered when an unstable atherosclerotic lesion is ruptured, leading to platelet activation and thrombus formation. Inflammatory mediators are responsible for lesion instability leading to rupture, and in recent years atherothrombosis and its underlying condition of atherosclerosis have come to be recognized as manifestations of inflammatory disease. Inflammatory mediators may therefore serve as early markers of atherothrombosis. Measurement of early markers may be used to predict future ischemic events and improve risk stratification in patients following diagnosis of atherothrombotic disease. In addition, detection of such markers may help to optimize the use of current therapies to manage atherothrombosis. Molecules that may serve as early markers of atherothrombotic disease include C-reactive protein, CD40 ligand, myeloperoxidase, pregnancy-associated plasma protein and plasminogen activator inhibitor-1. Early indications are that levels of these markers are influenced by therapies currently in use in the treatment of atherothrombotic conditions, including antiplatelet agents. Ongoing studies will provide further insight into routine assessment of inflammatory markers as a guide to the management of patients with atherothrombosis.

Irbesartan, an angiotensin type 1 receptor inhibitor, regulates the vascular oxidative state in patients with coronary artery disease.

OBJECTIVES: The aim of this study was to determine the effect of angiotensin II type 1 (AT(1)) receptor antagonists on pro-oxidant species observed in the pathogenesis of atherosclerosis. Parameters such as low-density lipoprotein (LDL) susceptibility, monocyte binding capacity, superoxide generation and lipid peroxidation were examined in the presence of the AT(1) receptor antagonist irbesartan. BACKGROUND: Low-density lipoprotein oxidation is a key component in the process of atherogenesis. This modification may involve various mechanisms, including changes in nitric oxide levels and superoxide levels. Additionally, compounds that suppress these mechanisms may retard or inhibit the pathogenesis of atherosclerosis. METHODS: Forty-seven patients with documented coronary artery disease were treated with irbesartan for a 12-week period. Patients were randomized to receive irbesartan or placebo. Lipid peroxidation, superoxide levels, monocyte binding and LDL oxidation were measured at 0, 4 and 12 weeks. Findings were statistically evaluated by two-way repeated measures analysis of variance with p < 0.05 being significant. RESULTS: Treatment with irbesartan significantly decreased the pro-oxidative environment seen in our study population. Lag time for LDL oxidation increased 32% at 12 weeks, suggesting an increased resistance of LDL modification in the serum. Thiobarbituric acid reactive substances activity indicated that lipid peroxidation decreased by 36% in comparison to placebo. In addition, superoxide levels and monocyte-binding capacity were also significantly reduced in coronary artery disease patients receiving irbesartan. CONCLUSIONS: Our results indicate that irbesartan may suppress the atherosclerotic process by inhibiting the intravascular oxidative state and the production of reactive oxygen species, compounds that may cause damage to the vasculature.

Signaling mechanisms of nuclear factor-kappab-mediated activation of inflammatory genes by 13-hydroperoxyoctadecadienoic acid in cultured vascular smooth muscle cells.

Oxidatively modified low density lipoprotein (LDL) has been implicated in the pathogenesis of atherosclerosis. LDL oxidation may be mediated by several factors, including cellular lipoxygenases. The lipoxygenase product of linoleic acid, 13-hydroperoxyoctadecadienoic acid (13-HPODE), is a significant component of oxidized LDL and has been shown to be present in atherosclerotic lesions. However, the mechanism of action of these oxidized lipids in vascular smooth muscle cells (VSMCs) is not clear. In the present study, we show that 13-HPODE leads to the activation of Ras as well as the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2, p38, and c-Jun amino-terminal kinase, in porcine VSMCs. 13-HPODE also specifically activated the oxidant stress-responsive transcription factor, nuclear factor-kappaB, but not activator protein-1 or activator protein-2. 13-HPODE-induced nuclear factor-kappaB DNA binding activity was blocked by an antioxidant, N-acetylcysteine, as well as an inhibitor of protein kinase C. 13-HPODE, but not the hydroxy product, 13-(S)-hydroxyoctadecadienoic acid, also dose-dependently increased vascular cell adhesion molecule-1 promoter activation. This was inhibited by an antioxidant as well as by inhibitors of Ras p38 mitogen-activated protein kinase and protein kinase C. Our results suggest that oxidized lipid components of oxidized LDL, such as 13-HPODE, may play a key role in the atherogenic process by inducing the transcriptional regulation of inflammatory genes in VSMCs via the activation of key signaling kinases.

Did the antioxidant trials fail to validate the oxidation hypothesis?

Most clinical trials on antioxidants using vitamin E or beta-carotene have failed to note any significant change in cardiovascular endpoints. The results of these studies have been interpreted as a setback for the oxidation hypothesis. An analysis of the hypothesis and the trials, however, points out major misconceptions about the hypothesis and unjustified outcome expectations. Wrong selection of patient population, endpoints that are incompatible with the hypothesis, poor choice of antioxidants, and lack of inclusion of biochemical markers of oxidative stress and markers of vascular response are some of the contributors to the "failure" of these trials.

Irbesartan, an angiotensin type 1 receptor inhibitor, regulates markers of inflammation in patients with premature atherosclerosis.

OBJECTIVES: This study assessed the role of angiotensin II type 1 (AT1) receptor antagonists on inflammatory mechanisms involved in atherogenesis. Specific inflammatory markers included solubilized tumor necrosis factor-alpha receptor II (sTNF-alphaRII), vascular cell adhesion molecule-1 (VCAM-1) and superoxide. In addition, the AT1 receptor blocker irbesartan was evaluated for its ability to suppress these markers in individuals with atherosclerosis. BACKGROUND: Mechanisms involved in the complex process of atherogenesis include alterations in the inflammatory responses. The use of compounds that suppress these responses may reduce the degree of damage seen in atherosclerosis. METHODS: With a cross-sectional study design, 33 normotensive patients with stable coronary artery disease (CAD) were treated with irbesartan for a 24-week period. These patients were compared against a control population with no known coronary atherosclerosis. Marker levels were measured by enzyme-linked immunosorbent assay technique and lucigenin chemiluminescence assay and statistically evaluated by two-way repeated measures analysis of variance. RESULTS: All patients with coronary artery disease had increased levels of inflammatory molecules over those of control patients. Treatment with irbesartan in these patients significantly reduced levels of inflammatory molecules measured. Soluble VCAM-1 levels were reduced by 36%; soluble TNF-alpha levels were reduced by 54% and superoxide level decreased by 52%. Maximal suppression of inflammatory markers by irbesartan therapy in patients with CAD was seen at 12 weeks. CONCLUSIONS: The effect of irbesartan on each inflammatory marker is significant. Our results show that use of irbesartan may retard the inflammatory process seen in premature forms of atherosclerosis.

Hyperglycemia-induced activation of nuclear transcription factor kappaB in vascular smooth muscle cells.

The transcriptional nuclear factor (NF)-kappaB can be activated by diverse stimuli such as cytokines, mitogens, oxidative stress, and lipids, leading to the transactivation of several genes that play important roles in the development of atherosclerosis. Because oxidative stress may play a key role in the pathogenesis of diabetic vascular disease, we have examined whether culture of porcine vascular smooth muscle cells (PVSMCs) under high glucose (HG) conditions (25 mmol/l) to simulate the diabetic state can lead to the activation of NF-kappaB, and also whether cytokine- or growth factor-induced NF-kappaB activation is altered by HG culture. We observed that PVSMCs cultured in HG showed significantly greater activation of NF-kappaB in the basal state compared with cells cultured in normal glucose (NG) (5.5 mmol/l). Treatment of the cells with cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin-1beta, or with growth factors, such as platelet-derived growth factor, insulin-like growth factor-I, and epidermal growth factor, all led to NF-kappaB activation in cells cultured in both NG and HG. However, their effects were markedly greater in HG. The augmented TNF-alpha-induced NF-kappaB activation in HG was associated with increased TNF-alpha-mediated transcriptional activation of the vascular cell adhesion molecule-1 promoter. Immunoblotting with an antibody to the p65 subunit of NF-kappaB indicated that the levels of this protein were higher in the nuclear extracts from cells cultured in HG compared with NG. Cells cultured in HG also produced significantly greater amounts of the reactive oxygen species superoxide. HG-induced NF-kappaB activation was inhibited by a protein kinase C inhibitor, calphostin C. These results suggest that hyperglycemia-induced activation of NF-kappaB in VSMCs may be a key mechanism for the accelerated vascular disease observed in diabetes.

Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells.

Decreased nitric oxide (NO) activity, the formation of reactive oxygen species, and increased endothelial expression of the redox-sensitive vascular cell adhesion molecule 1 (VCAM-1) gene in the vessel wall are early and characteristic features of atherosclerosis. To explore whether these phenomena are functionally interrelated, we tested the hypothesis that redox-sensitive VCAM-1 gene expression is regulated by a NO-sensitive mechanism. In early passaged human umbilical vein endothelial cells and human dermal microvascular endothelial cells, the NO donor diethylamine-NO (DETA-NO, 100 microM) reduced VCAM-1 gene expression induced by the cytokine tumor necrosis factor alpha (TNF-alpha, 100 units/ml) at the cell surface level by 65% and intracellular adhesion molecule 1 (ICAM-1) gene expression by 35%. E-selectin gene expression was not affected. No effect on expression of cell adhesion molecules was observed with DETA alone. Moreover, DETA-NO suppressed TNF-alpha-induced mRNA accumulation of VCAM-1 and TNF-alpha-mediated transcriptional activation of the human VCAM-1 promoter. Conversely, treatment with NG-monomethyl-L-arginine (L-NMMA, 1 mM), an inhibitor of NO synthesis, augmented cytokine induction of VCAM-1 and ICAM-1 mRNA accumulation. By gel mobility shift analysis, DETA-NO inhibited TNF-alpha activation of DNA binding protein activity to the VCAM-1 NF-kappa B like binding sites. Peroxy-fatty acids such as 13-hydroperoxydodecanoeic acid (linoleyl hydroperoxide) may serve as an intracellular signal for NF-kappa B activation. Using thin layer chromatography, DETA-NO (100 microM) suppressed formation of this metabolite, suggesting that DETA-NO modifies the reactivity of oxygen intermediates in the vascular endothelium. Through this mechanism, NO may function as an immunomodulator of the vessel wall and thus mediate inflammatory events involved in the pathogenesis of atherosclerosis.

Modified low density lipoprotein and its constituents augment cytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells.

Early features in the pathogenesis of atherosclerosis include accumulation of oxidized LDL (oxLDL) and endothelial expression of the vascular adhesion molecule VCAM-1. Because antioxidants inhibit endothelial VCAM-1 expression, we tested the hypothesis that oxLDL functions as a prooxidant signal in atherogenesis to augment VCAM-1 activation by inflammatory signals. Cultured human aortic endothelial cells (HAECs) or human umbilical vein endothelial cells (HUVECs) were incubated with unmodified LDL, oxLDL, or glycated LDL for 48 h. No change in VCAM-1, intercellular cell adhesion molecule-1 (ICAM-1), or E-selectin expression from control was observed by ELISA. However, dose-response and time course studies demonstrated that oxLDL enhanced VCAM-1 expression induced by the cytokin tumor necrosis factor alpha (TNF alpha) 63% in HAECs and 45% in HUVECs over unmodified LDL or control. Using flow cytometry analysis, oxLDL augmented TNF alpha-induced VCAM-1 expression in a uniform HAEC population. oxLDL had no effect on E-selection induction. oxLDL augmented TNF alpha-induced ICAM-1 expression 44% in HAECs but not in HUVECs. Glycated LDL augmented TNF alpha-induced VCAM-1 expression 35% in HAECs but not HUVECs. Similar results were obtained with 13-HPODE or lysophosphatidylcholine, significant components of oxLDL. 13-HPODE augmented TNF alpha-induced mRNA accumulation and transcriptional activation of VCAM-1 in HAECs. These results suggest that as long-term regulatory signals, specific oxidized fatty acid and phospholipid components of oxLDL augment the ability of vascular endothelial cells to express cytokine-mediated VCAM-1. These studies link oxidant signals conferred by oxLDL to oxidation-sensitive regulatory mechanisms controlling the expression of endothelial cell adhesion molecules involved in early atherosclerosis.

Cholesterol is required for the secretion of the very-low-density lipoprotein: in vivo studies.

Rats were fed for 1 week with a standard chow diet, a diet supplemented with lovastatin (0.1%), or a diet supplemented with both lovastatin and cholesterol (0.1/0.1%), to study effects of depletion of a putative hepatic metabolic pool of cholesterol on secretion of the very-low-density lipoprotein (VLDL) in the intact animal. Triton WR-1339 (50 mg/100 g body wt.) or the 0.9% NaCl vehicle alone was given intravenously via a sacral vein. Treatment with lovastatin decreased the secretion of all plasma VLDL lipids, the average decrease after 2 h for VLDL triacylglycerol, phospholipid, cholesterol and cholesteryl ester being 45%. When both lovastatin and cholesterol were included in the diet, the secretion of VLDL triacylglycerol and phospholipid was similar to that of control animals, while secretion of VLDL cholesterol and cholesteryl ester was increased. Treatment with lovastatin reduced the hepatic concentration of cholesteryl esters 42% without affecting free cholesterol. In separate experiments, in vivo synthesis of cholesterol was determined 1 h after intraperitoneal administration of 3H2O. Incorporation into hepatic and plasma free cholesterol and cholesteryl esters was greater in the rats fed lovastatin than in control animals, concurrent with decreased VLDL secretion. The metabolism of VLDL was determined in vivo by intravenous administration of 125I-VLDL. The fractional clearance rates of 125I-VLDL from the plasma were similar among the three experimental groups. Synthesis of hepatic triacylglycerol from [1-14C]oleate in vivo was similar in all treatment groups; incorporation into plasma triacylglycerol was reduced with lovastatin treatment and reversed partially by inclusion of 0.1% cholesterol in the lovastatin diet. Plasma concentrations of triacylglycerol followed patterns of incorporation of [1-14C]oleate. Triacylglycerol concentration in the liver increased when cholesterol was included in the diet. In companion experiments, incorporation of [1-14C]oleate into perfusate triacylglycerol in vitro was reduced with perfused livers from lovastatin-treated animals. In these experiments, oxidation of fatty acid into CO2 and perchloric acid-soluble counts was not affected by lovastatin, added either to the diet or to the perfusate in vitro. It appears, therefore, that lovastatin does not affect triacylglycerol synthesis or fatty acid oxidation, which per se might reduce formation and secretion of VLDL. These data, therefore, strengthen the hypothesis that reduced availability of cholesterol in a putative hepatic metabolic pool, required for secretion and transport of triacylglycerol in the VLDL, is a factor contributing to decreased secretion of the VLDL.