Inhaled Glucocorticosteroid and Long-Acting β<Subscript>2</Subscript>-Adrenoceptor Agonist Single-Inhaler Combination for Both Maintenance and Rescue Therapy

Despite aggressive fixed-dose (FD) combination therapy with inhaled glucocorticosteroids (ICS) and long acting beta(2)-adrenoceptor agonists (LABA), many patients with asthma remain suboptimally controlled, based on the need for rescue therapy and rates of severe exacerbations. The strategy of adjustable maintenance dosing (AMD) involves adjustment of the maintenance dose, (using a single combination [budesonide/formoterol] inhaler, Symbicort((R))) in response to variability of asthma control over time. The AMD strategy, like the FD approach, involves the use of a short-acting beta(2)-adrenoceptor agonist (SABA) for rapid relief of bronchospasm. The dose-response characteristics of budesonide/formoterol make the AMD strategy a feasible option that cannot be exploited with the combination of salmeterol/fluticasone propionate (Advair((R))). Several studies suggest that the AMD strategy is superior to a FD approach in terms of overall asthma control.Budesonide/formoterol in a single inhaler is as effective as albuterol (salbutamol) for relief of acute asthma episodes, a feature that makes it possible to use this combination for both maintenance and reliever therapy without the need for the use of a SABA. The single-inhaler strategy has been shown to be safe and more efficacious than FD therapy. In particular, the COSMOS study has demonstrated that exacerbation burden is reduced more effectively when the combination (budesonide/formoterol) single inhaler is used for both maintenance and relief compared with FD therapy with salmeterol/fluticasone and albuterol for rescue in patients with moderate-to-severe asthma. These findings suggest that we will have to reconsider our definition of reliever therapy for patients that require long-term therapy with combination ICS and LABA.The concept of single-inhaler therapy represents a paradigm shift in asthma management that has been validated in several large studies involving thousands of patients. The single-inhaler strategy represents one of the most significant advances in asthma management in many years, and one that appears ideal for adoption in primary care.     

Tolerability Profiles of Leukotriene Receptor Antagonists and Long-Acting β2-Adrenoceptor Agonists in Combination with Inhaled Corticosteroids for Treatment of Asthma: A Review

Inhaled corticosteroids, long-acting β₂-adrenoceptor agonists, and leukotriene receptor antagonists are widely used for treatment of asthma. Inhaled corticosteroids are recommended as first-line therapy, whereas long-acting β₂-adrenoceptor agonists and leukotriene receptor antagonists are indicated as add-on therapy in patients not adequately controlled with corticosteroids alone. A number of studies have investigated the efficacy of combinations of these drugs in asthma, but several issues concerning the safety of these treatments are highly debated. This review provides a critical appraisal of the tolerability profiles of long-acting β₂-agonists and leukotriene receptor antagonists used in combination with inhaled corticosteroids for the treatment of asthma.     

Long-Acting β<Subscript>2</Subscript>-Agonists

Salmeterol and formoterol are both long-acting β₂-adrenoceptor agonists (β₂-agonists). They both provide excellent bronchodilating and bronchoprotective effects in patients with asthma but their are some differences between these two long-acting β₂-agonists in vitro and in vivo. Formoterol has a greater potency and intrinsic activity than salmeterol, which can become especially apparent at higher doses than that clinically recommended, and in contracted bronchi. Long-term use of long-acting β₂-agonists can induce tolerance, which can be partially reversed with corticosteroids. Long-acting β₂-agonists have some anti-inflammatory effects in vitro, but data in vivo are less convincing. Compared with doubling the dose of inhaled corticosteroids, the addition of inhaled long-acting β₂-agonists to inhaled corticosteroids improves symptom control in patients with asthma and reduces both the exacerbation rate of asthma and hospital admission rate. No enhanced airway responsiveness or loss of perception of dyspnea has been observed with the use of inhaled long-acting β₂-agonists. Monotherapy with long-acting β₂-agonists is not recommended.     

Effect of β-Blockers on β<Subscript>3</Subscript>-Adrenoceptor Expression in Chronic Heart Failure

Objectives To investigate the expression of β₃-adrenoceptors in rats with chronic heart failure, and to explore the effect of β-blockers on β₃-adrenoceptor expression. Materials and methods Thirty-two male Wistar rats were divided into Sham (n = 10) and heart failure (n = 22) groups. The heart failure group was treated with normal saline (Heart Failure Control, n = 6), Metoprolol (n = 8) or Carvedilol (n = 8) for 3 months. Results The left ventricular end systolic pressure (LVESP) and the absolute values of maximal rate of rise and fall of left ventricular pressure (±dP/dt max) in the heart failure group were lower than in the Sham group (P < 0.01), whereas the left ventricular end diastolic pressure (LVEDP) was higher (P < 0.01). The LVESP and dP/dtmax in the Carvedilol group were higher than the Metoprolol group whereas LVEDP was lower (P < 0.01). The left ventricular mass index (LVMI) in the Carvedilol group was less than the Metoprolol and Heart Failure Control groups (P < 0.01). The level of β₃-adrenoceptor expression in the study groups was significantly higher than the Sham group (P < 0.01). β₃-adrenoceptor expression in the Carvedilol group was lower than the Heart Failure Control and Metoprolol groups (P < 0.01). Conclusion β₃-adrenoceptor expression is increased in the failing ventricles in rats. Carvedilol is more effective than Metoprolol for improving the hemodynamics and in attenuating ventricular remodeling after heart failure. Carvedilol, rather than Metoprolol, diminishes β₃-adrenoceptor expression in the failing ventricles.     

Clinical Efficacy of Inhaler Devices Containing β<Subscript>2</Subscript>-Agonist Bronchodilators in the Treatment of Asthma

Background: A number of different inhaler devices are available to deliver β₂-adrenoceptor agonist (β₂-agonist) bronchodilators in asthma. These include hydrofluoroalkane or chlorofluorocarbon (CFC)-free propelled pressurized metered-dose inhalers (pMDIs), many dry powder inhalers and breath-actuated inhalers. Objective: To determine the clinical efficacy of all available hand-held inhaler devices compared with the standard CFC-containing pMDI for the delivery of short-acting β₂-agonist bronchodilators in nonacute asthma in both children and adults. Methodology: A systematic review and meta-analysis was carried out of all available randomized, controlled trials (RCTs) using the standard pMDI compared with any other hand-held inhaler device, delivering short-acting β₂-agonist bronchodilators in patients with stable asthma. Results: One hundred and eighteen RCTs were included in this review. No clinical differences were found between the standard CFC-containing pMDI and 12 other hand-held inhaler devices for most outcome measures. We found no evidence of clinical differences between studies using either a 1 : 1 (pMDI: another inhaler) or a 2 : 1 dosing ratio. Conclusions: In patients with stable asthma, short-acting β₂-agonist bronchodilators in standard CFC-pMDIs are as effective as any other hand-held inhaler device; therefore the cheapest available device that the patient is able to use should always be considered. Pharmaceutical companies should in future submit to regulatory authorities clinical outcome data (as opposed to in vitro data) in support of any dosing schedules greater than 1 : 1 when compared with the standard pMDI. Clinical effectiveness studies that use an intention-to-treat analysis and report more patient-centered outcomes are required.     

Sandwich ELISA for hemoglobin A<Subscript>2</Subscript> quantification and identification of β-thalassemia carriers

Hemoglobin (Hb) A₂ (α₂δ₂) is a minor hemoglobin in human red blood cells. An abnormal increase in the level of HbA₂ is the most significant parameter in the diagnosis of β-thalassemia carriers. In this study, we produced two monoclonal antibodies (mAbs) that specifically react to the δ-globin chain of HbA₂. A sandwich type ELISA was developed employing the produced anti-HbA₂ mAbs. HbA₂ levels quantified by the developed sandwich ELISA were highly correlated with those obtained from the standard HPLC method (r = 0.934, p < 0.001). HbA₂ levels determined by the ELISA were 4.4 ± 1.9% in β-thalassemia heterozygotes compared to 1.4 ± 0.8, 1.9 ± 0.8, 1.5 ± 0.8 and 1.5 ± 0.6% in normal subjects, HbE heterozygotes, suspected α-thalassemia heterozygotes and HbE homozygotes, respectively. Using a cut-off value of 2.5%, β-thalassemia heterozygotes could be separated from non-β-thalassemia heterozygotes with the same accuracy as obtained using the standard HPLC method. More importantly, the developed ELISA was able to determine HbA₂ levels in HbE-bearing individuals which could not be done by the HPLC method. Our results suggest that this sandwich ELISA can be applied for mass screening for β-thalassemia heterozygotes, especially in resource-limited countries, where β-thalassemia is highly prevalent.     

Combination Inhalers Containing Inhaled Corticosteroids and Long-Acting β2-Agonists: Improved Clinical Efficacy and Dosing Options in Patients with Asthma

Combination therapy with inhaled corticosteroids (ICS) and long-acting β₂-agonists (LABA) is a recognized treatment for adults with moderate to severe asthma. The introduction of inhalers containing both an ICS and a LABA simplifies treatment and improves asthma control. This review discusses clinical evidence that budesonide/formoterol and salmeterol/fluticasone are effective and well tolerated in asthma treatment. Moreover, the rapid onset of effect and long duration of action of budesonide and formoterol make once-daily dosing, adjustable maintenance dosing, and the novel treatment strategy of using budesonide/formoterol for maintenance and as needed for symptom relief, valuable treatment options for patients with asthma.     

Taxifolin prevents β-amyloid-induced impairments of synaptic formation and deficits of memory via the inhibition of cytosolic phospholipase A<Subscript>2</Subscript>/prostaglandin E<Subscript>2</Subscript> content

Taxifolin is a potent flavonoid with anti-inflammatory activity. Taxifolin has been reported to decrease the accumulation of β-amyloid (Aβ), and reduce Aβ-induced neurotoxicity. However, the detail molecular mechanism of taxifolin against Aβ-induced neurotoxicity is largely unknown. In this study, we revealed the protective effects and the underlying mechanisms of taxifolin on the impairments of cognitive function and synapse formation induced by soluble Aβ oligomers. Our results showed that taxifolin prevented neuronal cell death in a concentration-dependent manner. The recognition memory in novel object recognition tasks and the spatial memory in Morris water maze tests are significantly lower in the Alzheimer’s disease (AD) model mice induced by hippocampal injection of Aβ₄₂. Taxifolin treatment prevented the recognitive and spatial memory deficits of the AD mice. 10 mg/kg taxifolin treatment also significantly prevented the decreased expression levels of PSD 95 induced by Aβ₄₂. Live cell imaging study showed that 2 h pre-treatment of taxifolin prevented the decrease in the number of filopodium and spine induced by Aβ₄₂ oligomers. Aβ₄₂ oligomers significantly increased the production of cytosolic phospholipase A₂ (cPLA₂), a crucial enzyme of pro-inflammatory mediator, and prostaglandin E₂ (PGE₂), a neuroinflammatory molecule. Taxifolin significantly reduced the content of cPLA₂ and PGE₂ induced by Aβ₄₂ both in the primary hippocampal neurons and hippocampal tissues. These results indicated that taxifolin might prevent Aβ₄₂ oligomer-induced synapse and cognitive impairments through decreasing cPLA₂ and PGE₂. Our study provided novel insights into the cellular mechanisms for the protective effects of taxifolin on AD.     

β<Subscript>2</Subscript>-Agonist Eutomers

β₂-adrenoceptor agonists (β₂-agonists) such as albuterol (salbutamol) and terbutaline and their long-acting analogs salmeterol and formoterol are widely used as bronchodilators in the treatment of asthma. They are chiral drugs historically marketed as racemic mixtures of an active (eutomer) and essentially inactive (distomer) stereoisomer. Despite their obvious therapeutic value and widespread use, β₂-agonists have been implicated, somewhat controversially, in causing an increase in asthma mortality and a deterioration of asthma control by a mechanism that remains elusive. Inherent toxicity of the distomers has been widely touted as an explanation and has given rise to pressure for the replacement of the racemates with pure eutomer formulations (the so-called chiral or racemic switch). This has culminated in the recent introduction into clinical practice of the single active stereoisomer of albuterol (levalbuterol) and the promise of other pure β₂-agonist eutomer formulations to follow. This article examines the evidence on which these chiral switches are based.Clinical studies designed to reveal negative effects of β₂-agonists have searched for reductions in lung function, increases in airway responsiveness to bronchoconstrictor mediators and worsening of asthma control. Crossover studies administering the pure stereoisomers and racemate of albuterol have not shown a clear superiority of the pure eutomer formulation over the racemate in terms of either bronchial hyperresponsiveness, tachyphylaxis to bronchoprotective effects or improvements in lung function. Clinical toxicity of β₂-agonist distomers on any aspect of asthmatic lung function has also not been demonstrated in the relatively short-term inhalational studies (single dose or repeated dose studies <1 week) that have been carried out.In animal studies, the administration of β₂-agonist racemates and distomers has been shown to enhance bronchial hyperresponsiveness but only in ovalbumin-sensitized animals where the relevance to humans is questionable.The pharmacokinetics and metabolism of β₂-agonist stereoisomers appear to be essentially similar whether administered as single stereoisomers or as racemates. Levalbuterol may be slightly more potent than an equivalent dose given as racemate, but there is some evidence that it forms a small amount of the distomer in vivo which detracts somewhat from its purported benefits over use of the racemate.Whilst there remains a clear need for studies of longer duration with sensitive clinical endpoints to evaluate the benefits of β₂-agonist eutomers and to investigate distomer toxicity, the chiral switch for β₂-agonists in general, and for albuterol in particular, does not appear to be justified on the basis of the evidence available to date.     

The roles of Transforming growth Factor Type β<Subscript>3</Subscript>(TGF-β<Subscript>3</Subscript>) and mast cells in the pathogenesis of scleroderma

Scleroderma is a connective tissue disorder characterised by excessive accumulation of collagen in the skin and internal organs. The most likely explanation for this process is local activation of collagen synthesis from fibroblasts. Our intention was to elucidate whether TGF-₃ and mast cells play a pathogenic role in abnormal connective tissue formation in scleroderma. In this study, skin biopsies from 20 patients with scleroderma and five from healthy individuals were studied by an indirect immunoperoxidase technique to determine the immunoreactivity of TGF-₃ in the dermis. In addition, skin samples were stained with toluidine blue to count the number of mast cells in scleroderma, and tissues were examined under the electron microscope to evaluate the ultrastructural changes. Increased TGF-₃ immunoreactivities were detected in the dermis in the patient's skin, suggesting the presence of a subpopulation responsible for the increased collagen production. Mast cell counts in the skin of patients with scleroderma were significantly greater (19.2 ± 4.1/unit) than those of normal controls (4.4 ± 1.2/unit). Ultrastructural observations indicated that there is a close relationship between the mast cells and fibroblasts. These results suggest that fibrosis in scleroderma could evolve through the activation of fibroblasts and the regulatory mechanisms that appear to modulate the behavior of these cells with respect to collagen production.AcknowledgementWe are grateful for the support of Professor M. Kaya in our work with the electron microscope and thank Professor E. Erten for supplying tissue samples.     

Pharmacological Stimulation of β <Subscript>2</Subscript>-adrenergic Receptors (β <Subscript>2</Subscript>AR) Enhances Therapeutic Effectiveness of β <Subscript>1</Subscript>AR Blockade in Rodent Dilated Ischemic Cardiomyopathy

Background. We have reported that β ₂ adrenoreceptor (β ₂AR) stimulation is anti-apoptotic, and has strong beneficial effect on cardiac remodeling in an experimental model of post myocardial infarction chronic heart failure (CHF) in rats. Here we investigate whether the addition of chronic pharmacological β ₂AR stimulation enhances the therapeutic effects of β ₁AR blockade on cardiac remodeling in the same model. Methods and Results. Metoprolol, a β ₁AR blocker, given alone (β ₁) or in combination with β ₂AR agonist, fenoterol (β ₁β ₂) were administered to rats via drinking water for 6 weeks, beginning 2 weeks following permanent coronary ligation. Progressive left ventricular (LV) remodeling of untreated animals, assessed by repeated echocardiography, occurred during the observation time, i.e., 42% and 25% increases in end-systolic and end-diastolic LV volumes respectively, 27% fall in ejection fraction, and 35% infarct expansion. Pressure-volume loop analyses at 2d and 8th post infarction weeks showed continuous deterioration of systolic and diastolic functions and arterio-ventricular mismatch. Histological evaluation at the end of 8 weeks revealed the MI expansion and hypertrophy of cardiomyocytes. β ₁β ₂ prevented LV remodeling, MI expansion and cardiomyocytes hypertrophy to a greater degree than β ₁, due, in large part, to a vasodilatory effect of β ₂AR stimulation and thus improvement of arterio-ventricular mismatch. The abnormal diastolic performance improved only in β ₁β ₂. β ₁β ₂ treatment reduced myocardial apoptosis throughout myocardium, but β ₁ reduced apoptopsis only in the areas remote from MI. Conclusion. The therapeutic effects of chronic β ₁AR blockade on cardiac remodeling of heart failure are enhanced and extended when supplemented with β ₂AR stimulation. This research was supported by the Intramural Research Program of the National Institute on Aging, NIH.     

Loss of β<Subscript>1</Subscript>D-integrin function in human ischemic cardiomyopathy

Integrins play a pivotal role in cardiomyocyte survival and function, with integrin loss leading to myocyte apoptosis and heart failure. The aim of this study was to characterize whether regulation of integrins may contribute to cardiac remodeling in human ischemic cardiomyopathy (ICM). Myocardial tissues of the left ventricle were obtained from patients with ICM (n = 8) undergoing cardiac transplantation and from unused donor hearts (NF, n = 8). In addition, tissue samples from patients with dilated cardiomyopathy (DCM, n = 5) were analyzed. Expression of integrins β₁D and β₃, the effector proteins focal adhesion kinase (FAK) and melusin, and FAK phosphorylation were examined by Western blotting, real-time-PCR and immunofluorescence analysis, respectively. β₁D-integrin protein was decreased in ICM vs. NF by 36%. β₁D-integrin mRNA levels and β₁D-integrin shedding were unchanged. Corresponding to β₁D-integrin regulation, FAK and phosphorylated FAK were decreased in ICM vs. NF by 54% and 49%, respectively. β₃-integrin and melusin were not altered in ICM. As a mediator of integrin effects, AKT kinase activity was examined. In parallel to β₁D-integrin and FAK, AKT activity was decreased in ICM by 44%. In contrast, none of the proteins were significantly altered in DCM compared to NF. Integrins and integrin signaling are regulated differentially in ICM and DCM with a decrease of β₁D-integrin and FAK in ICM. The loss of the β₁Dintegrin-FAK-complex in ICM was paralleled by a reduced AKT activity supporting in vitro data which demonstrate the pivotal role of intact integrin function in anti-apoptotic signaling and cell survival.     

Prevalence of Anticardiolipin and Anti-β<Subscript>2</Subscript>-Glycoprotein I Antibodies in Celiac Disease

The aim of this study was to evaluate the prevalence of anticardiolipin antibodies (aCL) and anti-β₂-glycoprotein I antibodies (aβ2GPI) in patients with celiac disease and to analyze the clinical features of antiphospholipid syndrome in these patients. We conducted a prospective case-control study based on the evaluation of IgG, IgM and IgA aCL, and IgG and IgA aβ2GPI in celiac disease patients and in controls. All patients were asked about any occurrence of thrombotic manifestations. In addition, women were asked about pregnancy morbidity. Fifty celiac disease patients and 50 healthy controls were studied. IgM aCL were not detected in study group or in controls. IgG aCL were found in two patients and in one control. IgA aCL were significantly more frequent in celiac disease patients compared with controls (13/50 (26%) vs. 2/50 (4%), p=0.004, OR [95% CI]=9.09 [1.81–50]). There was no statistically significant difference for the prevalence of IgG and IgA aβ2GPI between patients and controls. Clinical features of antiphospholipid syndrome were noted in two patients with negative antibodies. Prevalence of IgM and IgG aCL and of aβ2GPI were not increased in celiac disease. IgA aCL were more frequently detected in celiac disease. However, no clinical features of antiphospholipid syndrome were noted.     

α<Subscript>1</Subscript>-Antitrypsinmangel

α₁-antitrypsin deficiency is characterized by a pathologic reduction of the serum concentration of α₁-antitrypsin, the most important antiprotease in man. It is one of the most common hereditary diseases in Caucasians. Approximately 2% of obstructive airway diseases are caused by α₁-antitrypsin deficiency. Patients above 35 years may develop lung emphysema, especially in the lower lobes. Symptoms are those of chronic obstructive pulmonary disease such as cough, sputum expectoration, and progressive dyspnoea. Patients with homozygous defect often develop cholestatic hepatitis in the neonatal period. However, only few adult patients develop chronic liver disease up to liver cirrhosis with an elevated risk for malignant liver tumors. The diagnostic hallmark is the reduced serum concentration of α₁-antitrypsin while genetic testing proves the defect. An early recognition of the disease is decisive for prophylactic and therapeutic measures. Smoking should be stopped immediately. Treatment of lung disease includes physiotherapy, antiobstructive and antiinflammatory medication, augmentation with human α₁-antitrypsin and lung surgery including lung transplantation. Liver toxins should be avoided. Besides experimental therapeutic approaches, liver disease can only be treated by liver transplantation.     

In situ validation of VEGFR-2 and <Emphasis Type="Italic">α</Emphasis><Subscript><Emphasis Type="Italic">v</Emphasis></Subscript><Emphasis Type="Italic">ß</Emphasis><Subscript>3</Subscript> integrin as targets for breast lesion characterization

Vascular endothelial growth factor receptor 2 (VEGFR-2) and α _v ß ₃ integrin are the most frequently addressed targets in molecular imaging of tumor angiogenesis. In preclinical studies, molecular imaging of angiogenesis has shown potential to detect and differentiate benign and malignant lesions of the breast. Thus, in this retrospective clinical study employing patient tissues, the diagnostic value of VEGFR-2, α _v ß ₃ integrin and vascular area fraction for the diagnosis and differentiation of breast neoplasia was evaluated. To this end, tissue sections of breast cancer (n = 40), pre-invasive ductal carcinoma in situ (DCIS; n = 8), fibroadenoma (n = 40), radial scar (n = 6) and normal breast tissue (n = 40) were used to quantify (1) endothelial VEGFR-2, (2) endothelial α _v ß ₃ integrin and (3) total α _v ß ₃ integrin expression, as well as (4) the vascular area fraction. Sensitivity and specificity to differentiate benign from malignant lesions were calculated for each marker by receiver operating characteristics (ROC) analyses. Whereas vessel density, as commonly used, did not significantly differ between benign and malignant lesions (AUROC: 0.54), VEGFR-2 and α _v ß ₃ integrin levels were gradually up-regulated in carcinoma versus fibroadenoma versus healthy tissue. The highest diagnostic accuracy for differentiating carcinoma from fibroadenoma was found for total α _v ß ₃ integrin expression (AUROC: 0.76), followed by VEGFR-2 (AUROC: 0.71) and endothelial α _v ß ₃ integrin expression (AUROC: 0.68). In conclusion, total α _v ß ₃ integrin expression is the best discriminator between breast cancer, fibroadenoma and normal breast tissue. With respect to vascular targeting and molecular imaging of angiogenesis, endothelial VEGFR-2 appeared to be slightly superior to endothelial α _v ß ₃ for differentiating benign from cancerous lesions.     

Studies of the associations between functional β<Subscript>2</Subscript>-adrenergic receptor variants and obesity,hypertension and type 2 diabetes in 7,808 white subjects

Aims/hypothesis Functional and common Arg16Gly and Gln27Glu polymorphisms have been identified in ADRB2, the gene encoding the β₂-adrenergic receptor. These variants have previously been examined for association with obesity, hypertension and diabetes with inconclusive results. Materials and methods We investigated both of these variants in 7,808 unrelated, middle-aged white people for their association with obesity in a case–control study, quantitative trait analysis and meta-analysis. Moreover, both variants were investigated for their potential influence on measures of hypertension and type 2 diabetes by case–control and quantitative trait analyses. Results The present study did not find consistent evidence for an association of these β₂-adrenergic receptor variants with obesity or hypertension; neither did the quantitative trait analyses show any effect of the variants on obesity-related traits. However, both the Gly allele of the Arg16Gly variant and the Glu allele of the Gln27Glu variant showed nominal association with systolic blood pressure. Furthermore, there was a nominal association of the Arg16 allele frequency and genotype distribution with type 2 diabetes; however, no influence on quantitative biochemical phenotypes related to type 2 diabetes was found. A nominal association of the Arg/Gly genotype with the metabolic syndrome was also observed (p = 0.003). Logistic regression analyses provided no evidence of a synergistic or an additive effect of these variants on obesity, hypertension or diabetes. Conclusions/interpretation After studying 7,808 middle-aged white subjects, we were unable to demonstrate any consistent associations between two common amino acid polymorphisms of the β₂-adrenergic receptor and obesity, hypertension or type 2 diabetes.     

Shear stress inhibition of H<Subscript>2</Subscript>O<Subscript>2</Subscript> induced p66<Superscript>Shc</Superscript> phosphorylation by ASK1–JNK inactivation in endothelium

Shear stress protects endothelium from a variety of risk factors for vascular disease. Here, we demonstrate a novel mechanism whereby shear stress inhibited reactive oxygen species (ROS)-triggered signaling cascades in endothelial cells. Stimulation of bovine aortic endothelial cells (BAECs) with H₂O₂ induced a 3.07-fold increase in p66^Shc phosphorylation. This response was fully blocked by pretreatment of cells with specific JNK but not p38 or ERK MAP kinase inhibitor. Further study showed that knocking down of apoptosis signal-regulating kinase 1 (ASK1) by siRNA transfection in cells dramatically inhibited phosphorylation of JNK and p66^Shc elicited by H₂O₂. Pre-perfusion of BAECs cultured in silastic tubes with laminar flow generated by a servo-pump system for 30 min also significantly suppressed H₂O₂-induced phosphorylation of p66^Shc. This was accompanied by quantitatively similar inhibition of ASK1 and JNK phosphorylation and activation. These results suggested that shear stress protects endothelium against oxidant stress by suppression of ASK1–JNK-mediated p66^Shc phosphorylation.     

Lipoprotein-Associated Phospholipase A<Subscript>2</Subscript> and C-Reactive Protein for Measurement of Inflammatory Risk: Independent or Complementary?

The purpose of this article is to review the evidence concerning the utility of lipoprotein-associated phospholipase A₂ (Lp-PLA₂), a key promoter of vascular inflammation, as a biomarker of future risk of cardiovascular disease. In addition, the evidence of complementary action of Lp-PLA₂ and C-reactive protein (CRP) is evaluated. On balance, there is a great deal of consistency across studies supporting Lp-PLA₂ as a risk factor for coronary disease and ischemic stroke (independently of traditional risk factors and CRP) among persons with and without clinical coronary artery disease. On the other hand, there is yet limited and inconsistent evidence for a synergistic effect of Lp-PLA₂ and CRP on cardiovascular disease risk. Additional studies are thus needed before widespread Lp-PLA₂ and CRP testing with regard to incremental cardiovascular disease risk prediction can be recommended.