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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 (Clifton, N.J.) (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 detailImpaired glucose tolerance and insulin resistance in heart failure: underrecognized and undertreated?
Mamas, Mamas A.; Deaton, Christi; Rutter, Martin K. et al

in Journal of cardiac failure (2010), 16(9), 761-8

BACKGROUND: A link between diabetes mellitus (DM) and heart failure (HF) has been well-recognized for more than a century. HF is also closely linked to abnormal glucose regulation (AGR) and insulin ... [more ▼]

BACKGROUND: A link between diabetes mellitus (DM) and heart failure (HF) has been well-recognized for more than a century. HF is also closely linked to abnormal glucose regulation (AGR) and insulin resistance (IR) in patients without DM and, similarly, these conditions commonly coexist. In epidemiological studies, each condition appears to predict the other. The prevalence of AGR/IR in HF patients without DM is significantly underrecognized and, as yet, the optimal method for screening for these abnormalities in the outpatient setting is unclear. METHODS AND RESULTS: The purpose of this review is to overview the prevalence and prognostic impact of AGR and IR in HF patients without DM and discuss potential pathophysiological pathways that link these conditions with HF. The severity of glucose intolerance in patients with HF correlates with functional and clinical severity of HF and is an independent predictor of an adverse outcome. It is thought that changes in cardiac metabolism, including a switch from glucose metabolism toward fatty acid metabolism, may in part contribute to the pathophysiological processes associated with HF patients with AGR/IR. CONCLUSIONS: We discuss how pharmacological targeting of metabolic pathways in the myocardium of these patients with HF may represent novel therapeutic strategies in these at-risk patients. [less ▲]

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See detailWhat are the thromboembolic risks of heart failure combined with chronic or paroxysmal AF?
Caldwell, Jane Cochrane; Mamas, Mamas A.; Neyses, Ludwig UL et al

in Journal of cardiac failure (2010), 16(4), 340-7

BACKGROUND: Heart failure (HF) and atrial fibrillation (AF) are common disorders that frequently occur together and are associated with an increased risk of thromboembolism. This thromboembolic risk may ... [more ▼]

BACKGROUND: Heart failure (HF) and atrial fibrillation (AF) are common disorders that frequently occur together and are associated with an increased risk of thromboembolism. This thromboembolic risk may be reduced by anticoagulation with warfarin but not without introducing new hemorrhagic risks. METHODS AND RESULTS: Current guidelines recommend the use of anticoagulation in patients with HF and chronic AF and paroxysmal AF (PAF) that is symptomatic or frequent and prolonged enough to be detected by electrocardiogram. However, the evidence supporting these recommendations is weak and does not take account of research indicating that the prothrombotic risk is higher in more severe HF. CONCLUSIONS: An area not addressed by current guidelines is anticoagulation in patients with HF and short, asymptomatic episodes of AF. These issues need to be resolved with further studies using implanted devices to detect such asymptomatic PAF. [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 detailEvaluation of plasma membrane calcium/calmodulin-dependent ATPase isoform 4 as a potential target for fertility control.
Cartwright, Elizabeth J.; Neyses, Ludwig UL

in Handbook of experimental pharmacology (2010), (198), 79-95

The array of contraceptives currently available is clearly inadequate and does not meet consumer demands since it is estimated that up to a quarter of all pregnancies worldwide are unintended. There is ... [more ▼]

The array of contraceptives currently available is clearly inadequate and does not meet consumer demands since it is estimated that up to a quarter of all pregnancies worldwide are unintended. There is, therefore, an overwhelming global need to develop new effective, safe, ideally non-hormonal contraceptives for both male and female use. The contraceptive field, unlike other areas such as cancer, has a dearth of new targets. We have addressed this issue and propose that isoform 4 of the plasma membrane calcium ATPase is a potentially exciting novel target for fertility control. The plasma membrane calcium ATPase is a ubiquitously expressed calcium pump whose primary function in the majority of cells is to extrude calcium to the extracellular milieu. Two isoforms of this gene family, PMCA1 and PMCA4, are expressed in spermatozoa, with PMCA4 being the predominant isoform. Although this gene is ubiquitously expressed, its function is highly tissue-specific. Genetic deletion of PMCA4, in PMCA4 knockout mice, led to 100% infertility specifically in the male mutant mice due to a selective defect in sperm motility. It is important to note that the gene deletion did not affect normal mating characteristics in these mice. This phenotype was mimicked in wild-type sperm treated with the non-specific PMCA inhibitor 5-(and 6-) carboxyeosin diacetate succinimidyl ester; a proof-of-principle that inhibition of PMCA4 has potential importance in the control of fertility. This review outlines the potential for PMCA4 to be a novel target for fertility control by acting to inhibit sperm motility. It will outline the characteristics that make this target drugable and will describe methodologies to identify and validate novel inhibitors of this target. [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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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 : JTH (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 detailRas-association domain family member 1A (RASSF1A)-where the heart and cancer meet.
Oceandy, Delvac; Cartwright, Elizabeth J.; Neyses, Ludwig UL

in Trends in cardiovascular medicine (2009), 19(8), 262-7

The close relationship between signaling pathways regulating tumor growth and cardiac hypertrophy has attracted considerable interest. Although the involvement of proto-oncogenes in positively modulating ... [more ▼]

The close relationship between signaling pathways regulating tumor growth and cardiac hypertrophy has attracted considerable interest. Although the involvement of proto-oncogenes in positively modulating myocardial hypertrophy has long been recognized, little is known about factors that counterregulate them. In this article, we review the novel tumor suppressor Ras-association domain family protein isoform 1A (RASSF1A), which strongly inhibits the prohypertrophic Ras-Raf1-ERK1/2 pathway in the heart. RASSF1A interacts with a number of important signaling molecules regulating cell growth, survival, and apoptosis; therefore, it serves as a key adaptor molecule that integrates the upstream stimuli and transduces them to the selective downstream effectors. [less ▲]

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See detailAtrial fibrillation is under-recognized in chronic heart failure: insights from a heart failure cohort treated with cardiac resynchronization therapy.
Caldwell, Jane C.; Contractor, Hussain; Petkar, Sanjiv et al

in Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology (2009), 11(10), 1295-300

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with chronic heart failure (CHF). Under-detection of asymptomatic paroxysmal AF (PAF) underestimates the true burden of ... [more ▼]

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with chronic heart failure (CHF). Under-detection of asymptomatic paroxysmal AF (PAF) underestimates the true burden of AF in patients with CHF. We retrospectively studied the prevalence of asymptomatic PAF in 162 CHF patients through analysis of cardiac resynchronization therapy (CRT) device downloads to determine whether these episodes are associated with adverse outcomes. METHODS AND RESULTS: An episode of AF was defined by mode switching on CRT devices with an atrial rate >200 for at least 30 s. Of the 101 patients thought to be persistently in sinus rhythm (SR), 27% were found to have significant paroxysms of AF, with the cumulative percentage of time in the 'mode-switch mode' (i.e. the AF burden) of 1.6 +/- 0.9%. Mortality was 19.2% in patients with newly identified PAF with hospitalization and thrombo-embolism rates of 42.3 and 2.1%, respectively, compared with mortality of 10.4% with hospitalization and thrombo-embolism rates of 41.8 and 1.9%, respectively, in patients persistently in SR (P= NS). CONCLUSION: Analysis of data from CRT devices in a population of CHF patients with severe left ventricular dysfunction shows that a significant proportion of those perceived to be persistently in SR have undiagnosed paroxysms of AF but with relatively low burden. These episodes appear to be associated with a trend towards increased mortality but no effects on hospitalization or thrombo-embolism rates. [less ▲]

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See detailA meta-analysis of the prognostic significance of atrial fibrillation in chronic heart failure.
Mamas, Mamas A.; Caldwell, Jane C.; Chacko, Sanoj et al

in European journal of heart failure (2009), 11(7), 676-83

AIMS: Atrial fibrillation (AF) is one of the commonest sustained arrhythmias in chronic heart failure (CHF), although the prognostic implications of the presence of AF in CHF remain controversial. We have ... [more ▼]

AIMS: Atrial fibrillation (AF) is one of the commonest sustained arrhythmias in chronic heart failure (CHF), although the prognostic implications of the presence of AF in CHF remain controversial. We have therefore performed this meta-analysis to study the effects of the presence of AF on mortality in CHF patients. METHODS AND RESULTS: A systematic MEDLINE search for all randomized trials and observational studies in which the influence of AF on CHF mortality was investigated and meta-analysis of the mortality data was performed. A total of 16 studies were identified of which 7 were randomized trials and 9 were observational studies including 30,248 and 23,721 patients, respectively. An adjusted meta-analysis of the data revealed that the presence of AF is associated with an adverse effect on total mortality with an odds ratio (OR) of 1.40 [95% confidence interval (CI) 1.32-1.48, P < 0.0001] in randomized trials and an OR of 1.14 (95% CI 1.03-1.26, P < 0.05) in observational studies. This increase in mortality associated with the presence of AF was observed in subgroups of CHF patients with both preserved and impaired left ventricular (LV) systolic function. CONCLUSION: In conclusion, meta-analysis of 16 studies involving 53,969 patients suggests that the presence of AF is associated with an adverse prognosis in CHF irrespective of LV systolic function. [less ▲]

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See detailEstrogen receptor alpha interacts with 17beta-hydroxysteroid dehydrogenase type 10 in mitochondria.
Jazbutyte, Virginija; Kehl, Franz; Neyses, Ludwig UL et al

in Biochemical and biophysical research communications (2009), 384(4), 450-4

Estrogen receptor alpha (ERalpha) is present in the nucleus, the cytosol and in mitochondria. The rat ERalpha ligand binding domain was employed as bait in a bacterial two-hybrid screening of a human ... [more ▼]

Estrogen receptor alpha (ERalpha) is present in the nucleus, the cytosol and in mitochondria. The rat ERalpha ligand binding domain was employed as bait in a bacterial two-hybrid screening of a human heart cDNA library to detect novel protein-protein interaction partners of ERalpha in the heart. 17beta-Hydroxysteroid dehydrogenase type 10 (17beta-HSD10), which converts potent (17beta-estradiol) to less potent estrogens (estrone), co-localized with 17beta-HSD10 in the mitochondria of rat cardiac myocytes. GST pull-down experiments confirmed the interaction of ERalpha and 17beta-HSD10. These findings suggest that the ERalpha estrogen receptor might be involved in regulating intracellular estrogen levels by modulating 17beta-HSD10 activity. [less ▲]

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See detailSpecific role of neuronal nitric-oxide synthase when tethered to the plasma membrane calcium pump in regulating the beta-adrenergic signal in the myocardium.
Mohamed, Tamer M. A.; Oceandy, Delvac; Prehar, Sukhpal et al

in The Journal of biological chemistry (2009), 284(18), 12091-8

The cardiac neuronal nitric-oxide synthase (nNOS) has been described as a modulator of cardiac contractility. We have demonstrated previously that isoform 4b of the sarcolemmal calcium pump (PMCA4b) binds ... [more ▼]

The cardiac neuronal nitric-oxide synthase (nNOS) has been described as a modulator of cardiac contractility. We have demonstrated previously that isoform 4b of the sarcolemmal calcium pump (PMCA4b) binds to nNOS in the heart and that this complex regulates beta-adrenergic signal transmission in vivo. Here, we investigated whether the nNOS-PMCA4b complex serves as a specific signaling modulator in the heart. PMCA4b transgenic mice (PMCA4b-TG) showed a significant reduction in nNOS and total NOS activities as well as in cGMP levels in the heart compared with their wild type (WT) littermates. In contrast, PMCA4b-TG hearts showed an elevation in cAMP levels compared with the WT. Adult cardiomyocytes isolated from PMCA4b-TG mice demonstrated a 3-fold increase in Ser(16) phospholamban (PLB) phosphorylation as well as Ser(22) and Ser(23) cardiac troponin I (cTnI) phosphorylation at base line compared with the WT. In addition, the relative induction of PLB phosphorylation and cTnI phosphorylation following isoproterenol treatment was severely reduced in PMCA4b-TG myocytes, explaining the blunted physiological response to the beta-adrenergic stimulation. In keeping with the data from the transgenic animals, neonatal rat cardiomyocytes overexpressing PMCA4b showed a significant reduction in nitric oxide and cGMP levels. This was accompanied by an increase in cAMP levels, which led to an increase in both PLB and cTnI phosphorylation at base line. Elevated cAMP levels were likely due to the modulation of cardiac phosphodiesterase, which determined the balance between cGMP and cAMP following PMCA4b overexpression. In conclusion, these results showed that the nNOS-PMCA4b complex regulates contractility via cAMP and phosphorylation of both PLB and cTnI. [less ▲]

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See detailUse of the Heartrail II catheter as a distal stent delivery device; an extended case series.
Mamas, Mamas A.; Eichhofer, Jonas; Hendry, Cara et al

in EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology (2009), 5(2), 265-71

AIMS: The Terumo Heartrail catheter (Terumo Corp., Tokyo, Japan) allows extra deep catheter intubation of coronary vessels and has been shown to be useful in CTO lesions. The aim of this study is to ... [more ▼]

AIMS: The Terumo Heartrail catheter (Terumo Corp., Tokyo, Japan) allows extra deep catheter intubation of coronary vessels and has been shown to be useful in CTO lesions. The aim of this study is to assess the safety and efficacy of using the Heartrail II catheter as a distal stent delivery system in PCI following failure of conventional techniques. METHODS AND RESULTS: We prospectively identified cases performed over a 15-month period in which a Heartrail catheter was used to facilitate stent delivery following failure of conventional techniques. Stent delivery using the Heartrail catheter was performed in 35 cases and was successful in 31 cases. Success rates of 100% in grafts, 95% in RCA, 80% in LAD and 60% in circumflex cases were recorded respectively. Successful stent delivery was associated with intubation depth, with 29/29 succeeding when the intubation depth was > 2 cm and failure in 4/5 cases when the intubation depth <or= 2 cm. There were no complications related to deep intubation of the catheter. CONCLUSIONS: Use of the Heartrail catheter is safe and highly effective for aiding stent delivery across proximal obstructions in both left and right coronary systems. The small number of unsuccessful cases were related to inability of the catheter to traverse stenotic proximal obstructions within 2 cm of the RCA and LCA origins. [less ▲]

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See detailThe cardiovascular phenotype of a mouse model of acromegaly.
Izzard, Ashley S.; Emerson, Michael; Prehar, Sukhpal et al

in Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society (2009), 19(5), 413-9

BACKGROUND: Although, it is accepted that there is an excess of cardiovascular mortality in acromegaly, it is uncertain whether this is due to the direct effects of growth hormone-induced-cardiomyopathy ... [more ▼]

BACKGROUND: Although, it is accepted that there is an excess of cardiovascular mortality in acromegaly, it is uncertain whether this is due to the direct effects of growth hormone-induced-cardiomyopathy or is a consequence of atherosclerosis secondary to the metabolic syndrome often observed in this condition. Direct comparison of a mouse model of acromegaly to a mouse model of Laron's syndrome allowed us to carry out detailed phenotyping and better understand the role GH plays in the circulatory system. METHODS AND RESULTS: Transgenic mice that overexpress the growth hormone gene (GH) developed gigantism, including insulin resistance and higher blood pressures commensurate with increased body mass. In these giant mice, the hearts were hypertrophied but haemodynamic studies suggested contractile function was normal. Segments of small arteries mounted in a pressure myograph showed vascular wall hypertrophy but a preserved lumen diameter. Vascular contractile function was normal. Mice in which the GH receptor gene was disrupted or 'knocked out' were dwarf and had low blood pressure, small hearts and blood vessels but a normally functioning circulation. Correlations of body mass with cardiovascular parameters suggested that blood pressure and structural characteristics develop in line with body size. CONCLUSION: In this transgenic mouse model of acromegaly, there is cardiac and vascular hypertrophy commensurate with GH excess but normal function. Our findings support the contention that the excess mortality in this condition may be due to the development of hypertrophic cardiomyopathy rather than increased rates of atherosclerotic coronary artery disease. [less ▲]

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See detailTumor suppressor Ras-association domain family 1 isoform A is a novel regulator of cardiac hypertrophy.
Oceandy, Delvac; Pickard, Adam; Prehar, Sukhpal et al

in Circulation (2009), 120(7), 607-16

BACKGROUND: Ras signaling regulates a number of important processes in the heart, including cell growth and hypertrophy. Although it is known that defective Ras signaling is associated with Noonan ... [more ▼]

BACKGROUND: Ras signaling regulates a number of important processes in the heart, including cell growth and hypertrophy. Although it is known that defective Ras signaling is associated with Noonan, Costello, and other syndromes that are characterized by tumor formation and cardiac hypertrophy, little is known about factors that may control it. Here we investigate the role of Ras effector Ras-association domain family 1 isoform A (RASSF1A) in regulating myocardial hypertrophy. METHODS AND RESULTS: A significant downregulation of RASSF1A expression was observed in hypertrophic mouse hearts, as well as in failing human hearts. To further investigate the role of RASSF1A in cardiac (patho)physiology, we used RASSF1A knock-out (RASSF1A(-)(/)(-)) mice and neonatal rat cardiomyocytes with adenoviral overexpression of RASSF1A. Ablation of RASSF1A in mice significantly enhanced the hypertrophic response to transverse aortic constriction (64.2% increase in heart weight/body weight ratio in RASSF1A(-)(/)(-) mice compared with 32.4% in wild type). Consistent with the in vivo data, overexpression of RASSF1A in cardiomyocytes markedly reduced the cellular hypertrophic response to phenylephrine stimulation. Analysis of molecular signaling events in isolated cardiomyocytes indicated that RASSF1A inhibited extracellular regulated kinase 1/2 activation, likely by blocking the binding of Raf1 to active Ras. CONCLUSIONS: Our data establish RASSF1A as a novel inhibitor of cardiac hypertrophy by modulating the extracellular regulated kinase 1/2 pathway. [less ▲]

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See detailCardiac-specific deletion of mkk4 reveals its role in pathological hypertrophic remodeling but not in physiological cardiac growth.
Liu, Wei; Zi, Min; Jin, Jiawei et al

in Circulation Research (2009), 104(7), 905-14

Mitogen-activated protein kinase kinase (MKK)4 is a critical member of the mitogen-activated protein kinase family. It is able to activate the c-Jun NH(2)-terminal protein kinase (JNK) and p38 mitogen ... [more ▼]

Mitogen-activated protein kinase kinase (MKK)4 is a critical member of the mitogen-activated protein kinase family. It is able to activate the c-Jun NH(2)-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase in response to environmental stresses. JNK and p38 are strongly implicated in pathological cardiac hypertrophy and heart failure; however, the regulatory mechanism whereby the upstream kinase MKK4 activates these signaling cascades in the heart is unknown. To elucidate the biological function of MKK4, we generated mice with a cardiac myocyte-specific deletion of mkk4 (MKK4(cko) mice). In response to pressure overload or chronic beta-adrenergic stimulation, upregulated NFAT (nuclear factor of activated T-cell) transcriptional activity associated with exacerbated cardiac hypertrophy and the appearance of apoptotic cardiomyocytes were observed in MKK4(cko) mice. However, when subjected to swimming exercise, MKK4(cko) mice displayed a similar level of physiological cardiac hypertrophy compared to controls (MKK4(f/f)). In addition, we also discovered that MKK4 expression was significantly reduced in heart failure patients. In conclusion, this study demonstrates for the first time that MKK4 is a key mediator which prevents the transition from an adaptive response to maladaptive cardiac hypertrophy likely involving the regulation of the NFAT signaling pathway. [less ▲]

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See detailPhysiological implications of the interaction between the plasma membrane calcium pump and nNOS.
Cartwright, Elizabeth J.; Oceandy, Delvac; Neyses, Ludwig UL

in Pflugers Archiv : European journal of physiology (2009), 457(3), 665-71

The tight regulation of intracellular calcium levels is essential for the normal function of a great many cellular processes, and disruption of this regulation, resulting in sustained increases in ... [more ▼]

The tight regulation of intracellular calcium levels is essential for the normal function of a great many cellular processes, and disruption of this regulation, resulting in sustained increases in intracellular-free calcium, has been associated with numerous diseases. One of the several transporters involved in calcium homeostasis is a P-type ATPase known as the plasma membrane calcium/calmodulin-dependent ATPase (PMCA) which is involved in calcium extrusion from the cytosol to the extracellular compartment. It has long been established that in many cell types, in particular non-excitable cells, the primary role of PMCA is in the bulk transport of intracellular calcium; however, its role in excitable cells is less clear. In the heart, for example, calcium is essential for contractile function as well as being a key messenger in signal transduction pathways; however, the mechanisms by which the cardiomyocyte distinguishes between these roles of calcium remain unclear. It is perhaps the transporters not involved in the contractile cycle (such as PMCA) that are able to carry non-contractile signals. This review will highlight the role of PMCA as a modulator of signal transduction pathways and in particular the role of isoform 4 in the regulation of the nitric oxide signalling pathway. [less ▲]

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See detailHow common is asymptomatic paroxysmal atrial fibrillation in chronic heart failure?
Caldwell, Jane; Mamas, Mamas; Garratt, Clifford et al

in Scandinavian cardiovascular journal : SCJ (2008), 42(6), 366367

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See detailExtensive catheter-induced aortic dissection.
Mamas, M. A.; Alonso, A.; Neyses, Ludwig UL

in The Canadian journal of cardiology (2008), 24(2), 9-10

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See detailCardiovascular manifestations associated with influenza virus infection.
Mamas, Mamas Andreas; Fraser, Doug; Neyses, Ludwig UL

in International journal of cardiology (2008), 130(3), 304-9

Influenza accounts for 3 to 5 million cases of severe illness and up to 300,000 deaths annually. Cardiovascular involvement in acute influenza infection can occur through direct effects of the virus on ... [more ▼]

Influenza accounts for 3 to 5 million cases of severe illness and up to 300,000 deaths annually. Cardiovascular involvement in acute influenza infection can occur through direct effects of the virus on the myocardium or through exacerbation of existing cardiovascular disease. Epidemiological studies have demonstrated an association between influenza epidemics and cardiovascular mortality and a decrease in cardiovascular mortality in high risk patients has been demonstrated following vaccination with influenza vaccine. Influenza is a recognised cause of myocarditis which can lead to significant impairment of cardiac function and mortality. With recent concerns regarding another potential global pandemic of influenza the huge potential for cardiovascular morbidity and mortality is discussed. [less ▲]

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