References of "Neyses, Ludwig 50002752"
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See detailCa2+ signalling in cardiovascular disease: the role of the plasma membrane calcium pumps.
Cartwright, Elizabeth J.; Oceandy, Delvac; Austin, Clare et al

in Science China Life Sciences (2011), 54(8), 691-8

The plasma membrane calcium ATPases (PMCA) are a family of genes which extrude Ca(2+) from the cell and are involved in the maintenance of intracellular free calcium levels and/or with Ca(2+) signalling ... [more ▼]

The plasma membrane calcium ATPases (PMCA) are a family of genes which extrude Ca(2+) from the cell and are involved in the maintenance of intracellular free calcium levels and/or with Ca(2+) signalling, depending on the cell type. In the cardiovascular system, Ca(2+) is not only essential for contraction and relaxation but also has a vital role as a second messenger in signal transduction pathways. A complex array of mechanisms regulate intracellular free calcium levels in the heart and vasculature and a failure in these systems to maintain normal Ca(2+) homeostasis has been linked to both heart failure and hypertension. This article focuses on the functions of PMCA, in particular isoform 4 (PMCA4), in the heart and vasculature and the reported links between PMCAs and contractile function, cardiac hypertrophy, cardiac rhythm and sudden cardiac death, and blood pressure control and hypertension. It is becoming clear that this family of calcium extrusion pumps have essential roles in both cardiovascular health and disease. [less ▲]

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See detailThe effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial.
Cleland, John G. F.; Teerlink, John R.; Senior, Roxy et al

in Lancet (2011), 378(9792), 676-83

BACKGROUND: Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are ... [more ▼]

BACKGROUND: Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. METHODS: We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. FINDINGS: 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9.7 mL) were recorded, associated with a small reduction in heart rate (up to 2.7 beats per min; p<0.0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0.0026) and end-diastolic volumes (16 mL, p=0.0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. INTERPRETATION: Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. FUNDING: Cytokinetics Inc. [less ▲]

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See detailThe role of metabolites and metabolomics in clinically applicable biomarkers of disease.
Mamas, Mamas; Dunn, Warwick B.; Neyses, Ludwig UL et al

in Archives of toxicology (2011), 85(1), 5-17

Metabolomics allows the simultaneous and relative quantification of thousands of different metabolites within a given sample using sensitive and specific methodologies such as gas or liquid chromatography ... [more ▼]

Metabolomics allows the simultaneous and relative quantification of thousands of different metabolites within a given sample using sensitive and specific methodologies such as gas or liquid chromatography coupled to mass spectrometry, typically in discovery phases of studies. Biomarkers are biological characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathological processes or pharmacologic responses to a therapeutic intervention. Biomarkers are widely used in clinical practice for the diagnosis, assessment of severity and response to therapy in a number of clinical disease states. In human studies, metabolomics has been applied to define biomarkers related to prognosis or diagnosis of a disease or drug toxicity/efficacy and in doing so hopes to provide greater pathophysiological understanding of disease or therapeutic toxicity/efficacy. This review discusses the application of metabolomics in the discovery and subsequent application of biomarkers in the diagnosis and management of inborn errors of metabolism, cardiovascular disease and cancer. We critically appraise how novel biomarkers discovered through metabolomic analysis may be utilized in future clinical practice by addressing the following three fundamental questions: (1) Can the clinician measure them? (2) Do they add new information? (3) Do they help the clinician to manage patients? Although a number of novel biomarkers have been discovered through metabolomic studies of human diseases in the last decade, none have currently made the transition to routine use in clinical practice. Metabolites identified from these early studies will need to form the basis of larger, prospective, externally validated studies in clinical cohorts for their future use as biomarkers. At this stage, the absolute quantification of these biomarkers will need to be assessed epidemiologically, as will the ultimate deployment in the clinic via routine biochemistry, dip stick or similar rapid at- or near-patient care technologies. [less ▲]

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See detailA comparison of drug-eluting stents versus bare metal stents in saphenous vein graft PCI outcomes: a meta-analysis.
Mamas, Mamas A.; Foley, James; Nair, Satheesh et al

in Journal of interventional cardiology (2011), 24(2), 172-80

AIMS: Studies demonstrate that percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is associated with reduced revascularization and major adverse cardiac events (MACE) rates compared ... [more ▼]

AIMS: Studies demonstrate that percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is associated with reduced revascularization and major adverse cardiac events (MACE) rates compared to bare metal stents (BMS) in native coronary vessels. Optimal PCI treatment of saphenous vein graft (SVG) lesions remains unclear despite SVG procedures representing up to 10% of PCI cases. We therefore performed a meta-analysis to compare outcomes between BMS and DES in SVG PCI. METHODS AND RESULTS: A search (2004-2009) of MEDLINE and conference proceedings for all relevant studies comparing mortality and MACE outcomes in DES versus BMS in SVG PCI and meta-analysis of the data was performed. Twenty studies were identified from 2005 to 2009 enrolling a total of 5,296 patients. Meta-analysis revealed a decrease in mortality associated with DES use, odds ratio (OR) 0.68; 95% confidence interval (CI) 0.53-0.88; P = 0.004. Similarly, MACE (OR 0.64; 95% CI 0.51-0.82; P < 0.001), total lesion revascularization (OR 0.60; 95% CI 0.43-0.83; P = 0.002), and total vessel revascularization (OR 0.57; 95% CI 0.41-0.80; P = 0.001) were significantly decreased in the patients in which DES were used compared to BMS. This reduction in mortality and MACE events associated with DES use appears to be limited to registry studies and not randomized controlled studies. CONCLUSIONS: Our meta-analysis suggests DES use to be safe in SVG PCI and associated with reduced mortality and MACE rates with reductions in revascularization also observed. [less ▲]

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See detailLocal signals with global impacts and clinical implications: lessons from the plasma membrane calcium pump (PMCA4).
Oceandy, Delvac; Mohamed, Tamer M. A.; Cartwright, Elizabeth J. et al

in Biochimica et biophysica acta (2011), 1813(5), 974-8

Calcium has been unequivocally regarded as a key signal messenger in almost every cell type. Calcium regulates a number of important cellular functions including cell growth, myofilament contraction, cell ... [more ▼]

Calcium has been unequivocally regarded as a key signal messenger in almost every cell type. Calcium regulates a number of important cellular functions including cell growth, myofilament contraction, cell survival and apoptosis as well as gene transcription. A complex regulatory mechanism of cellular calcium is needed to fine tune the precise calcium concentration in each subcellular location and also to transmit the signals carried by the calcium pool to the correct end target. In this article we will review the recently emerging role of the plasma membrane calcium/calmodulin dependent ATPase isoform 4 (PMCA4) in regulating calcium signalling. We will then focus on the function of this molecule in cardiomyocytes, in which PMCA4 forms protein-protein interactions with several key signalling molecules. Recent evidence has shown in vivo physiological functionalities and possible clinical implications of the PMCA4 signalling complex. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. [less ▲]

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See detailMitogen-activated protein kinase kinase 4 deficiency in cardiomyocytes causes connexin 43 reduction and couples hypertrophic signals to ventricular arrhythmogenesis.
Zi, Min; Kimura, Tomomi E.; Liu, Wei et al

in The Journal of biological chemistry (2011), 286(20), 17821-30

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See detailDrug eluting stents for the treatment of bare metal in-stent restenosis: long-term outcomes in real world practice.
Appleby, Clare E.; Khattar, Raj S.; Morgan, Kenneth et al

in EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology (2011), 6(6), 748-53

AIMS: Drug eluting stents (DES) have had a great impact in reducing in-stent restenosis (ISR) in de novo lesions. However, long-term data regarding effectiveness and safety of these stents in treating ... [more ▼]

AIMS: Drug eluting stents (DES) have had a great impact in reducing in-stent restenosis (ISR) in de novo lesions. However, long-term data regarding effectiveness and safety of these stents in treating bare metal stent (BMS) ISR are limited. We report long-term clinical outcomes in a cohort of patients with BMS-ISR treated with DES between April 2002 and December 2003 at our institution. METHODS AND RESULTS: Sixty-nine consecutive patients with significant BMS-ISR were treated with DES implantation. Sirolimus DES were used in 43 patients and paclitaxel DES in 26. All patients were followed up to determine the incidence of major adverse cardiac event (MACE) rates (all-cause death, myocardial infarction, or target vessel revascularisation [TVR]), angina class and the need for clinically driven angiography. The mean age of the cohort was 58.6 +/- 10.8 years; 68% were male, 33% were diabetic, 50% had hypertension, 78% were on statin therapy and 59% were current (19%) or previous (41%) smokers. The clinical presentation of ISR was with chronic stable angina in 54 patients, 12 had a non-ST elevation acute coronary syndrome and three presented with ST-elevation myocardial infarction. Multivessel stenting was performed in 21 patients and bifurcation stenting in seven patients. Over a mean follow period of 4.9 years, the first event MACE rate was 20% (17 events in 14 patients - eight deaths of which three were cardiac, two non-fatal myocardial infarctions and seven TVR). Excluding non-cardiac death, the adjusted MACE rate was 14.5% (12 events in 10 patients). At long-term follow-up, mean Canadian angina class decreased from 2.3 +/- 0.7 pre-procedure to 1.2 +/- 0.4, 65% of patients were angina free and 80% were free of MACE. No differences in long-term outcomes were observed between patients receiving paclitaxel and sirolimus DES. CONCLUSIONS: The use of DES for the treatment of BMS-ISR is safe and effective over a mean follow-up period of nearly five years. To our knowledge, this represents the longest follow-up data of real world patients treated in a single interventional centre. [less ▲]

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See detailIntegration of metabolomics in heart disease and diabetes research: current achievements and future outlook.
Dunn, Warwick B.; Goodacre, Royston; Neyses, Ludwig UL et al

in Bioanalysis (2011), 3(19), 2205-22

Metabolomics is an emerging and powerful discipline that provides an accurate and dynamic picture of the phenotype of mammalian systems through the study of endogenous and exogenous metabolites in cells ... [more ▼]

Metabolomics is an emerging and powerful discipline that provides an accurate and dynamic picture of the phenotype of mammalian systems through the study of endogenous and exogenous metabolites in cells, tissues, culture supernatants as well as biofluids. In the last 5 years an increase in the number of metabolomic investigations of cardiovascular diseases and diabetes has been observed. In this article the experimental strategies applied and recent examples of their application in disease and drug efficacy/toxicity biomarker detection and the employment for the discovery of new molecular pathophysiological processes related to disease onset and progression, as well as their usefulness in drug efficacy/toxicity, will be reviewed. An outlook of the requirements for future successes will also be discussed. [less ▲]

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See detailAutomated workflows for accurate mass-based putative metabolite identification in LC/MS-derived metabolomic datasets.
Brown, Marie; Wedge, David C.; Goodacre, Royston et al

in Bioinformatics (2011), 27(8), 1108-12

MOTIVATION: The study of metabolites (metabolomics) is increasingly being applied to investigate microbial, plant, environmental and mammalian systems. One of the limiting factors is that of chemically ... [more ▼]

MOTIVATION: The study of metabolites (metabolomics) is increasingly being applied to investigate microbial, plant, environmental and mammalian systems. One of the limiting factors is that of chemically identifying metabolites from mass spectrometric signals present in complex datasets. RESULTS: Three workflows have been developed to allow for the rapid, automated and high-throughput annotation and putative metabolite identification of electrospray LC-MS-derived metabolomic datasets. The collection of workflows are defined as PUTMEDID_LCMS and perform feature annotation, matching of accurate m/z to the accurate mass of neutral molecules and associated molecular formula and matching of the molecular formulae to a reference file of metabolites. The software is independent of the instrument and data pre-processing applied. The number of false positives is reduced by eliminating the inaccurate matching of many artifact, isotope, multiply charged and complex adduct peaks through complex interrogation of experimental data. AVAILABILITY: The workflows, standard operating procedure and further information are publicly available at http://www.mcisb.org/resources/putmedid.html. CONTACT: warwick.dunn@manchester.ac.uk. [less ▲]

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See detailPlasma membrane calcium pump (PMCA4)-neuronal nitric-oxide synthase complex regulates cardiac contractility through modulation of a compartmentalized cyclic nucleotide microdomain.
Mohamed, Tamer M. A.; Oceandy, Delvac; Zi, Min et al

in The Journal of biological chemistry (2011), 286(48), 41520-9

Identification of the signaling pathways that regulate cyclic nucleotide microdomains is essential to our understanding of cardiac physiology and pathophysiology. Although there is growing evidence that ... [more ▼]

Identification of the signaling pathways that regulate cyclic nucleotide microdomains is essential to our understanding of cardiac physiology and pathophysiology. Although there is growing evidence that the plasma membrane Ca(2+)/calmodulin-dependent ATPase 4 (PMCA4) is a regulator of neuronal nitric-oxide synthase, the physiological consequence of this regulation is unclear. We therefore tested the hypothesis that PMCA4 has a key structural role in tethering neuronal nitric-oxide synthase to a highly compartmentalized domain in the cardiac cell membrane. This structural role has functional consequences on cAMP and cGMP signaling in a PMCA4-governed microdomain, which ultimately regulates cardiac contractility. In vivo contractility and calcium amplitude were increased in PMCA4 knock-out animals (PMCA4(-/-)) with no change in diastolic relaxation or the rate of calcium decay, showing that PMCA4 has a function distinct from beat-to-beat calcium transport. Surprisingly, in PMCA4(-/-), over 36% of membrane-associated neuronal nitric-oxide synthase (nNOS) protein and activity was delocalized to the cytosol with no change in total nNOS protein, resulting in a significant decrease in microdomain cGMP, which in turn led to a significant elevation in local cAMP levels through a decrease in PDE2 activity (measured by FRET-based sensors). This resulted in increased L-type calcium channel activity and ryanodine receptor phosphorylation and hence increased contractility. In the heart, in addition to subsarcolemmal calcium transport, PMCA4 acts as a structural molecule that maintains the spatial and functional integrity of the nNOS signaling complex in a defined microdomain. This has profound consequences for the regulation of local cyclic nucleotide and hence cardiac beta-adrenergic signaling. [less ▲]

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See detailCalcium signaling dysfunction in heart disease.
Cartwright, Elizabeth J.; Mohamed, Tamer; Oceandy, Delvac et al

in BioFactors (Oxford, England) (2011), 37(3), 175-81

In the heart, Ca(2+) is crucial for the regulation of contraction and intracellular signaling, processes, which are vital to the functioning of the healthy heart. Ca(2+) -activated signaling pathways must ... [more ▼]

In the heart, Ca(2+) is crucial for the regulation of contraction and intracellular signaling, processes, which are vital to the functioning of the healthy heart. Ca(2+) -activated signaling pathways must function against a background of large, rapid, and tightly regulated changes in intracellular free Ca(2+) concentrations during each contraction and relaxation cycle. This review highlights a number of proteins that regulate signaling Ca(2+) in both normal and pathological conditions including cardiac hypertrophy and heart failure, and discusses how these pathways are not regulated by the marked elevation in free intracellular calcium ([Ca(2+) ](i)) during contraction but require smaller sustained increases in Ca(2+) concentration. In addition, we present published evidence that the pool of Ca(2+) that regulates signaling is compartmentalized into distinct cellular microdomains and is thus distinct from that regulating contraction. [less ▲]

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See detailDeprivation of MKK7 in cardiomyocytes provokes heart failure in mice when exposed to pressure overload.
Liu, Wei; Zi, Min; Chi, Hongbo et al

in Journal of Molecular and Cellular Cardiology (2011), 50(4), 702-11

There is little doubt that members of mitogen-activated protein kinase (MAPK) families play key roles in the transition from adaptive hypertrophic remodeling to heart failure. Mitogen-activated protein ... [more ▼]

There is little doubt that members of mitogen-activated protein kinase (MAPK) families play key roles in the transition from adaptive hypertrophic remodeling to heart failure. Mitogen-activated protein kinase kinase 7 (MKK7) is a critical component of stress-activated MAP kinase signaling pathway. The role of MKK7 plays in mediating cardiac remodeling in response to load stress has yet to be defined. Herein, we investigate the role of MKK7 in regulating cardiac remodeling in response to pressure overload. We generated and examined the phenotype of mice with cardiomyocyte-specific deletion of the mkk7 gene (MKK7(cko)). Following one week of pressure overload, MKK7(cko) mice exhibited characteristic phenotypes of heart failure evidenced by deterioration in ventricular function and pulmonary congestion. Cell death assays revealed an increased prevalence of cardiomyocyte apoptosis in the MKK7(cko) heart, in which elevated p53 levels and attenuated expression of manganese superoxide dismutase (MnSOD) were found. Moreover, extensive interstitial fibrosis was discovered in the knockout heart likely attributable to upregulation of transforming growth factor beta (TGF-beta) signaling. These results reveal an essential role of MKK7 in cardiomyocytes for protecting the heart from hypertrophic insults thereby preventing the transition to heart failure. [less ▲]

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See detailWhat influences physical activity in people with heart failure?: a qualitative study.
Tierney, Stephanie; Elwers, Heather; Sange, Chandbi et al

in International journal of nursing studies (2011), 48(10), 1234-43

BACKGROUND: Research has highlighted the benefits of physical activity for people with stable heart failure in improving morbidity and quality of life. However, adherence to exercise among this patient ... [more ▼]

BACKGROUND: Research has highlighted the benefits of physical activity for people with stable heart failure in improving morbidity and quality of life. However, adherence to exercise among this patient group is low. Barriers and enablers to sustained physical activity for individuals with heart failure have been little investigated. OBJECTIVES: To explore reasons why people with heart failure do and do not engage in regular physical activity. DESIGN: A qualitative, interview-based investigation. SETTINGS: Three heart failure clinics held at hospitals in the UK. PARTICIPANTS: Purposive sampling was adopted to provide maximum variation in terms of gender, age, heart failure duration and severity, and current activity levels. Twenty two patients (7=female) were interviewed, aged between 53 and 82 years. METHODS: Semi-structured interviews were conducted via telephone. These were recorded and transcribed verbatim. Framework analysis was applied to collected data. RESULTS: Interviewees' narratives suggested that adopting positive health behaviours was complex, affected by internal and external factors. This was reflected in the four themes identified during analysis: fluctuating health; mental outlook; others' expectations; environmental influences. Failure to exercise arose because of symptoms, co-morbidities, poor sense of self as active and/or lack of perceived benefit. Likewise, encouragement from others and inclement weather affected exercising. CONCLUSIONS: Areas identified during interviews as influencing activity levels relate to those commonly found in behavioural change theories, namely perceived costs and benefits, self-efficacy and social support. These are concepts that practitioners may consider when devising interventions to assist patients with heart failure in undertaking and maintaining regular exercise patterns. [less ▲]

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See detailMeasurement of plasma membrane calcium-calmodulin-dependent ATPase (PMCA) activity.
Mohamed, Tamer M. A.; Baudoin-Stanley, Florence M.; Abou-Leisa, Riham et al

in Methods in Molecular Biology (2010), 637

The plasma membrane calcium-calmodulin-dependent ATPase (PMCA) is a calcium-extruding enzymatic pump that ejects calcium from the cytoplasm to the extracellular compartment. Although in excitable cells ... [more ▼]

The plasma membrane calcium-calmodulin-dependent ATPase (PMCA) is a calcium-extruding enzymatic pump that ejects calcium from the cytoplasm to the extracellular compartment. Although in excitable cells such as skeletal and cardiac muscle cells PMCA has been shown to play only a minor role in regulating global intracellular calcium concentration, increasing evidence points to an important role for PMCA in signal transduction, in particular in the nitric oxide signaling pathway. Moreover, recent evidence has shown the functional importance of PMCA in mediating cardiac contractility and vascular tone. Here we describe a method in determining PMCA activity in the microsomal membrane preparation from cultured cells that overexpress specific isoform of PMCA by using modified coupled enzyme assay. [less ▲]

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See detailThe plasma membrane calcium ATPase modulates calcium homeostasis, intracellular signaling events and function in platelets.
Jones, S.; Solomon, A.; Sanz-Rosa, D. et al

in Journal of Thrombosis and Haemostasis (2010), 8(12), 2766-74

BACKGROUND: The plasma membrane calcium ATPase (PMCA) regulates localized signaling events in a variety of cell types, although its functional role in platelets remains undefined. OBJECTIVES: To ... [more ▼]

BACKGROUND: The plasma membrane calcium ATPase (PMCA) regulates localized signaling events in a variety of cell types, although its functional role in platelets remains undefined. OBJECTIVES: To investigate the role of PMCA in determining platelet intracellular calcium concentration ([Ca(2)(+) ](i) ) at rest and following agonist stimulation, and to define the corresponding effects upon different stages of platelet activation. METHODS: [Ca(2)(+) ](i) was continuously measured in Fura-2-loaded platelets and in vitro and in vivo functional analyses performed in the presence of the PMCA inhibitor carboxyeosin (CE). RESULTS: Concentrations of CE that selectively inhibited Ca(2)(+) extrusion through PMCA were established in human platelets. [Ca(2)(+) ](i) was elevated by CE in resting platelets, although collagen-stimulated Ca(2)(+) release was reduced. Impaired Ca(2)(+) mobilization upon agonist stimulation was accompanied by reduced dense granule secretion and impaired platelet aggregation. Platelet aggregation responses were also reduced in PMCA4(-/-) mice and in an in vivo mouse model of platelet thromboembolism. Conversely, inhibition of PMCA promoted the early and later stages of platelet activation, observed as enhanced adhesion to fibrinogen, and accelerated clot retraction. Investigations into the signaling mechanisms underlying CE-mediated inhibition of platelet aggregation implicated cGMP-independent vasodilator-stimulated phosphoprotein phosphorylation. CONCLUSIONS: Disruption of PMCA activity perturbs platelet Ca(2)(+) homeostasis and function in a time-dependent manner, demonstrating that PMCA differentially regulates Ca(2)(+) -dependent signaling events, and hence function, throughout the platelet activation process. [less ▲]

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See detailPlasma membrane calcium ATPase proteins as novel regulators of signal transduction pathways.
Holton, Mary Louisa; Wang, Weiguang; Emerson, Michael et al

in World Journal of Biological Chemistry (2010), 1(6), 201-8

Emerging evidence suggests that plasma membrane calcium ATPases (PMCAs) play a key role as regulators of calcium-triggered signal transduction pathways via interaction with partner proteins. PMCAs ... [more ▼]

Emerging evidence suggests that plasma membrane calcium ATPases (PMCAs) play a key role as regulators of calcium-triggered signal transduction pathways via interaction with partner proteins. PMCAs regulate these pathways by targeting specific proteins to cellular sub-domains where the levels of intracellular free calcium are kept low by the calcium ejection properties of PMCAs. According to this model, PMCAs have been shown to interact functionally with the calcium-sensitive proteins neuronal nitric oxide synthase, calmodulin-dependent serine protein kinase, calcineurin and endothelial nitric oxidase synthase. Transgenic animals with altered expression of PMCAs are being used to evaluate the physiological significance of these interactions. To date, PMCA interactions with calcium-dependent partner proteins have been demonstrated to play a crucial role in the pathophysiology of the cardiovascular system via regulation of the nitric oxide and calcineurin/nuclear factor of activated T cells pathways. This new evidence suggests that PMCAs play a more sophisticated role than the mere ejection of calcium from the cells, by acting as modulators of signaling transduction pathways. [less ▲]

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See detailResting Pd/Pa measured with intracoronary pressure wire strongly predicts fractional flow reserve.
Mamas, Mamas A.; Horner, Simon; Welch, Elise et al

in The Journal of invasive cardiology (2010), 22(6), 260-5

OBJECTIVE: To investigate the relationship between resting distal coronary pressure to aortic pressure ratio (Pd/Pa) and fractional flow reserve (FFR) obtained during maximal hyperemia. BACKGROUND: FFR is ... [more ▼]

OBJECTIVE: To investigate the relationship between resting distal coronary pressure to aortic pressure ratio (Pd/Pa) and fractional flow reserve (FFR) obtained during maximal hyperemia. BACKGROUND: FFR is an invasive index of the functional severity of a coronary artery stenosis determined from coronary pressure measurements. It is generally believed that there is little correlation between resting Pd/Pa and FFR obtained during maximal hyperemia. We have therefore studied this relationship in a large cohort of patients who had undergone pressure- wire assessments. METHODS: 528 consecutive pressure-wire studies performed in 483 patients over a 2-year period were retrospectively analyzed. RESULTS: A linear correlation between resting Pd/Pa and FFR post-pharmacological hyperemia was observed (rho = 0.74; p < 0.0001). When a FFR of < or = 0.75 (or < or = 0.80 as per FAME) was defined as positive, a resting Pd/Pa of < or = 0.85 (< or = 0.87) had a positive predictive value (PPV) of 95% (94.6%), while a resting Pd/Pa of > or = 0.93 (> or = 0.96) had a negative predictive value (NPV) of 95.7% (93%). CONCLUSIONS: We demonstrate a strong correlation between resting Pd/Pa and FFR. Resting values of Pd/Pa can be used to predict a positive FFR result with relatively high PPV and NPV. This may potentially obviate the need for adenosine infusion in a proportion of pressure-wire studies. [less ▲]

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See detailTargeted deletion of the extracellular signal-regulated protein kinase 5 attenuates hypertrophic response and promotes pressure overload-induced apoptosis in the heart.
Kimura, Tomomi E.; Jin, Jiawei; Zi, Min et al

in Circulation Research (2010), 106(5), 961-70

RATIONALE: Mitogen-activated protein kinase (MAPK) pathways provide a critical connection between extrinsic and intrinsic signals to cardiac hypertrophy. Extracellular signal-regulated protein kinase (ERK ... [more ▼]

RATIONALE: Mitogen-activated protein kinase (MAPK) pathways provide a critical connection between extrinsic and intrinsic signals to cardiac hypertrophy. Extracellular signal-regulated protein kinase (ERK)5, an atypical MAPK is activated in the heart by pressure overload. However, the role of ERK5 plays in regulating hypertrophic growth and hypertrophy-induced apoptosis is not completely understood. OBJECTIVE: Herein, we investigate the in vivo role and signaling mechanism whereby ERK5 regulates cardiac hypertrophy and hypertrophy-induced apoptosis. METHODS AND RESULTS: We generated and examined the phenotypes of mice with cardiomyocyte-specific deletion of the erk5 gene (ERK5(cko)). In response to hypertrophic stress, ERK5(cko) mice developed less hypertrophic growth and fibrosis than controls. However, increased apoptosis together with upregulated expression levels of p53 and Bad were observed in the mutant hearts. Consistently, we found that silencing ERK5 expression or specific inhibition of its kinase activity using BIX02189 in neonatal rat cardiomyocytes (NRCMs) reduced myocyte enhancer factor (MEF)2 transcriptional activity and blunted hypertrophic responses. Furthermore, the inhibition of MEF2 activity in NRCMs using a non-DNA binding mutant form of MEF2 was found to attenuate the ERK5-regulated hypertrophic response. CONCLUSIONS: These results reveal an important function of ERK5 in cardiac hypertrophic remodeling and cardiomyocyte survival. The role of ERK5 in hypertrophic remodeling is likely to be mediated via the regulation of MEF2 activity. [less ▲]

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See detailUse of the sheathless guide catheter during routine transradial percutaneous coronary intervention: a feasibility study.
Mamas, Mamas; D'Souza, Savio; Hendry, Cara et al

in Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions (2010), 75(4), 596-602

OBJECTIVE: The aim of this study is to investigate the feasibility of using a 6.5 Fr sheathless guide catheter as a default system in transradial (TRA) percutaneous coronary intervention (PCI). BACKGROUND ... [more ▼]

OBJECTIVE: The aim of this study is to investigate the feasibility of using a 6.5 Fr sheathless guide catheter as a default system in transradial (TRA) percutaneous coronary intervention (PCI). BACKGROUND: TRA PCI has been shown to reduce mortality rates through a reduction in access site related bleeding complications compared with procedures performed though a femoral approach. Complications associated with the TRA route increase with the size of sheath used. These complications may be reduced by the use of a sheathless guide catheter system (Asahi Intecc, Japan) that is 1-2 Fr sizes smaller in diameter than the corresponding introducer sheath. METHODS: We performed PCI in 100 consecutive cases using 6.5 Fr sheathless guides to determine the procedural success, rates of symptomatic radial spasm and radial occlusion. RESULTS: Procedural success using the 6.5 Fr sheathless guide catheter system was 100% with no cases requiring conversion to a conventional guide and catheter system. There were no procedural complications recorded associated with the use of the catheter. Adjunctive devices used in this cohort included IVUS, stent delivery catheters, distal protection devices, and simple thrombectomy catheters. The rate of radial spasm was 5% and the rate of radial occlusion at 2 months was 2%. CONCLUSION: Use of the 6.5 Fr sheathless guide catheter system, which has an outer diameter <5 Fr sheath, as the default system in routine PCI is feasible with a high rate of procedural success via the radial artery. [less ▲]

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