References of "Neyses, Ludwig 50002752"
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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 detailNeuronal nitric oxide synthase signaling in the heart is regulated by the sarcolemmal calcium pump 4b.
Oceandy, Delvac; Cartwright, Elizabeth J.; Emerson, Michael et al

in Circulation (2007), 115(4), 483-92

BACKGROUND: Neuronal nitric oxide synthase (nNOS) has recently been shown to be a major regulator of cardiac contractility. In a cellular system, we have previously shown that nNOS is regulated by the ... [more ▼]

BACKGROUND: Neuronal nitric oxide synthase (nNOS) has recently been shown to be a major regulator of cardiac contractility. In a cellular system, we have previously shown that nNOS is regulated by the isoform 4b of plasma membrane calcium/calmodulin-dependent ATPase (PMCA4b) through direct interaction mediated by a PDZ domain (PSD 95, Drosophilia Discs large protein and Zona occludens-1) on nNOS and a cognate ligand on PMCA4b. It remains unknown, however, whether this interaction has physiological relevance in the heart in vivo. METHODS AND RESULTS: We generated 2 strains of transgenic mice overexpressing either human PMCA4b or PMCA ct120 in the heart. PMCA ct120 is a highly active mutant form of the pump that does not interact with or modulate nNOS function. Calcium was extruded normally from PMCA4b-overexpressing cardiomyocytes, but in vivo, overexpression of PMCA4b reduced the beta-adrenergic contractile response. This attenuated response was not observed in ct120 transgenic mice. Treatment with a specific nNOS inhibitor (N omega-propyl-L-arginine) reduced the beta-adrenergic response in wild-type and ct120 transgenic mice to levels comparable to those of PMCA4b transgenic animals. No differences in lusitropic response were observed in either transgenic strain compared with wild-type littermates. CONCLUSIONS: These data demonstrate the physiological relevance of the interaction between PMCA4b and nNOS and suggests its signaling role in the heart. [less ▲]

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See detailBoth estrogen receptor subtypes, alpha and beta, attenuate cardiovascular remodeling in aldosterone salt-treated rats.
Arias-Loza, Paula-Anahi; Hu, Kai; Dienesch, Charlotte et al

in Hypertension (2007), 50(2), 432-8

Experimental and population-based studies indicate that female gender and estrogens protect the cardiovascular system against aldosterone-induced injury. Understanding the function of estrogens in heart ... [more ▼]

Experimental and population-based studies indicate that female gender and estrogens protect the cardiovascular system against aldosterone-induced injury. Understanding the function of estrogens in heart disease requires more precise information on the role of both estrogen receptor (ER) subtypes, ERalpha and ERbeta. Therefore, we determined whether selective activation of ERalpha or of ERbeta would confer redundant, specific, or opposing effects on cardiovascular remodeling in aldosterone salt-treated rats. The ERalpha agonist 16alpha-LE2, the ERbeta agonist 8beta-VE2, and the nonselective estrogen receptor agonist 17beta-estradiol lowered elevated blood pressure, cardiac mass, and cardiac myocyte cross-sectional areas, as well as increased perivascular collagen accumulation and vascular osteopontin expression in ovariectomized rats receiving chronic aldosterone infusion plus a high-salt diet for 8 weeks. Uterus atrophy was prevented by 16alpha-LE2 and 17beta-estradiol but not by 8beta-VE2. Cardiac proteome analyses by 2D gel electrophoresis, mass spectrometry, and peptide sequencing identified specific subsets of proteins involved in cardiac contractility, energy metabolism, cellular stress response and extracellular matrix formation that were regulated in opposite directions by aldosterone salt treatment and by different estrogen receptor agonists. We conclude that activation of either ERalpha or ERbeta protects the cardiovascular system against the detrimental effects of aldosterone salt treatment and confers redundant, as well as specific, effects on cardiac protein expression. Nonfeminizing ERbeta agonists such as 8beta-VE2 have a therapeutic potential in the treatment of hypertensive heart disease. [less ▲]

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See detailPromoter polymorphism of the matrix metalloproteinase 3 gene is associated with regurgitation and left ventricular remodelling in mitral valve prolapse patients.
Oceandy, Delvac; Yusoff, Rahal; Baudoin, Florence M. et al

in European journal of heart failure (2007), 9(10), 1010-7

BACKGROUND AND AIMS: Mitral valve prolapse (MVP) is common and highly variable in its severity, but the factors underlying this variability are unclear. In this study, we tested the hypothesis that ... [more ▼]

BACKGROUND AND AIMS: Mitral valve prolapse (MVP) is common and highly variable in its severity, but the factors underlying this variability are unclear. In this study, we tested the hypothesis that polymorphic variations in Matrix Metalloproteinase (MMP) genes might be predictors of left ventricular (LV) remodelling and severity of regurgitation in MVP. METHODS AND RESULTS: 70 MVP patients and 75 normal subjects were studied. We performed comprehensive echocardiography and analyzed promoter polymorphisms in the MMP-1 and MMP-3 genes. The MMP-3 -1612 5A/6A polymorphism showed strong associations with indices of mitral regurgitation and LV remodelling: Patients with 5A/5A allele had more pronounced remodelling and more severe mitral regurgitation than patients with the 6A/6A or 5A/6A alleles. We then cloned and sequenced 2 kb fragments of MMP-3 promoter from patients with 5A/5A and 6A/6A genotypes and found 4 different sets of promoter haplotypes. Promoter analysis showed that higher promoter activity was related to a more severe phenotype and that the haplotype variants had a more dominant role in determining the activity. CONCLUSIONS: Our data identifies the MMP-3 promoter haplotype as a novel marker of an adverse disease course in MVP, suggesting the presence of genetic determinants for the severity of MVP. [less ▲]

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See detailThe interaction between endogenous calcineurin and the plasma membrane calcium-dependent ATPase is isoform specific in breast cancer cells.
Holton, Marylouisa; Yang, Di; Wang, Weiguang et al

in FEBS letters (2007), 581(21), 4115-9

Plasma membrane calcium/calmodulin-dependent ATPases (PMCAs) are high affinity calcium pumps that extrude calcium from the cell. Emerging evidence suggests a novel role for PMCAs as regulators of calcium ... [more ▼]

Plasma membrane calcium/calmodulin-dependent ATPases (PMCAs) are high affinity calcium pumps that extrude calcium from the cell. Emerging evidence suggests a novel role for PMCAs as regulators of calcium/calmodulin-dependent signal transduction pathways via interaction with specific partner proteins. In this work, we demonstrate that endogenous human PMCA2 and -4 both interact with the signal transduction phosphatase, calcineurin, whereas, no interaction was detected with PMCA1. The strongest interaction was observed between PMCA2 and calcineurin. The domain of PMCA2 involved in the interaction is equivalent to that reported for PMCA4b. PMCA2-calcineurin interaction results in inhibition of the calcineurin/nuclear factor of activated T-cells signalling pathway. [less ▲]

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See detailPlasma membrane calcium ATPase and its relationship to nitric oxide signaling in the heart.
Cartwright, Elizabeth J.; Oceandy, Delvac; Neyses, Ludwig UL

in Annals of the New York Academy of Sciences (2007), 1099

The plasma membrane calcium/calmodulin-dependent ATPase (PMCA) is a ubiquitously expressed calcium-extruding enzymatic pump. In the majority of cells the main function of PMCA is as the only system to ... [more ▼]

The plasma membrane calcium/calmodulin-dependent ATPase (PMCA) is a ubiquitously expressed calcium-extruding enzymatic pump. In the majority of cells the main function of PMCA is as the only system to extrude calcium from the cytosol, however, in the excitable cells of the heart it has only a minor role in the bulk removal of calcium compared to the sodium-calcium exchanger. There is increasing evidence to suggest that PMCA has an additional role as a potential modulator of a number of signal transduction pathways. Of key interest in the heart is the functional interaction between the calcium/calmodulin-dependent enzyme neuronal nitric oxide synthase (nNOS) and isoform 4 of PMCA. Nitric oxide production from nNOS is known to be important in the regulation of excitation-contraction (EC) coupling and subsequently contractility. This article will focus on recent evidence suggesting that PMCA4 has a regulatory role in the nitric oxide signaling pathway in the heart. [less ▲]

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See detailTargeting the sarcolemmal calcium pump: a potential novel strategy for the treatment of cardiovascular disease.
Oceandy, Delvac; Mamas, Mamas A.; Neyses, Ludwig UL

in Cardiovascular & hematological agents in medicinal chemistry (2007), 5(4), 300-4

Intracellular calcium dynamics play a very important role in mediating contraction and signalling in cardiomyocytes and vascular smooth muscle cells. A number of calcium transporters have been identified ... [more ▼]

Intracellular calcium dynamics play a very important role in mediating contraction and signalling in cardiomyocytes and vascular smooth muscle cells. A number of calcium transporters have been identified that orchestrate a complex process of excitation-contraction coupling and molecular signalling. Despite the variability of the calcium transporters expressed in cardiomyocytes, most calcium channel blockers used therapeutically target the L-type calcium channel and exhibit antihypertensive and/or vasodilating activities. Recently, another calcium pump which is located in the sarcolemma has been shown to mediate cardiac contractility and vascular tone. Interestingly, this sarcolemmal calcium pump (also known as Plasma Membrane Calcium/calmodulin dependent ATPase or PMCA) exerts its function not by altering global calcium concentration, but by mediating signal transduction pathways. This review will discuss recent advances that support the key roles of PMCA as signalling molecule and the potential to target this calcium pump as a novel approach for the treatment of cardiovascular disease. [less ▲]

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See detailThe regulatory function of plasma-membrane Ca(2+)-ATPase (PMCA) in the heart.
Oceandy, D.; Stanley, P. J.; Cartwright, E. J. et al

in Biochemical Society transactions (2007), 35(Pt 5), 927-30

The PMCA (plasma-membrane Ca(2+)-ATPase) is a ubiquitously expressed calcium-extruding enzymatic pump important in the control of intracellular calcium concentration. Unlike in non-excitable cells, where ... [more ▼]

The PMCA (plasma-membrane Ca(2+)-ATPase) is a ubiquitously expressed calcium-extruding enzymatic pump important in the control of intracellular calcium concentration. Unlike in non-excitable cells, where PMCA is the only system for calcium extrusion, in excitable cells, such as cardiomyocytes, PMCA has been shown to play only a minor role in calcium homoeostasis compared with the NCX (sodium/calcium exchanger), another system of calcium extrusion. However, increasing evidence points to an important role for PMCA in signal transduction; of particular interest in cardiac physiology is the modulation of nNOS (neuronal nitric oxide synthase) by isoform 4b of PMCA. In the present paper, we will discuss recent advances that support a key role for PMCA4 in modulating the nitric oxide signalling pathway in the heart. [less ▲]

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See detailA change of scene: Ludwig Neyses, MD. Interview by Mark Nicholls.
Neyses, Ludwig UL; Neyes, Ludwig

in Circulation (2007), 116(3), 13-5

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See detailConditional neuronal nitric oxide synthase overexpression impairs myocardial contractility.
Burkard, Natalie; Rokita, Adam G.; Kaufmann, Susann G. et al

in Circulation Research (2007), 100(3), 32-44

The role of the neuronal NO synthase (nNOS or NOS1) enzyme in the control of cardiac function still remains unclear. Results from nNOS(-/-) mice or from pharmacological inhibition of nNOS are ... [more ▼]

The role of the neuronal NO synthase (nNOS or NOS1) enzyme in the control of cardiac function still remains unclear. Results from nNOS(-/-) mice or from pharmacological inhibition of nNOS are contradictory and do not pay tribute to the fact that probably spatial confinement of the nNOS enzyme is of major importance. We hypothesize that the close proximity of nNOS and certain effector molecules like L-type Ca(2+)-channels has an impact on myocardial contractility. To test this, we generated a new transgenic mouse model allowing conditional, myocardial specific nNOS overexpression. Western blot analysis of transgenic nNOS overexpression showed a 6-fold increase in nNOS protein expression compared with noninduced littermates (n=12; P<0.01). Measuring of total NOS activity by conversion of [(3)H]-l-arginine to [(3)H]-l-citrulline showed a 30% increase in nNOS overexpressing mice (n=18; P<0.05). After a 2 week induction, nNOS overexpression mice showed reduced myocardial contractility. In vivo examinations of the nNOS overexpressing mice revealed a 17+/-3% decrease of +dp/dt(max) compared with noninduced mice (P<0.05). Likewise, ejection fraction was reduced significantly (42% versus 65%; n=15; P<0.05). Interestingly, coimmunoprecipitation experiments indicated interaction of nNOS with SR Ca(2+)ATPase and additionally with L-type Ca(2+)- channels in nNOS overexpressing animals. Accordingly, in adult isolated cardiac myocytes, I(Ca,L) density was significantly decreased in the nNOS overexpressing cells. Intracellular Ca(2+)-transients and fractional shortening in cardiomyocytes were also clearly impaired in nNOS overexpressing mice versus noninduced littermates. In conclusion, conditional myocardial specific overexpression of nNOS in a transgenic animal model reduced myocardial contractility. We suggest that nNOS might suppress the function of L-type Ca(2+)-channels and in turn reduces Ca(2+)-transients which accounts for the negative inotropic effect. [less ▲]

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See detailSerum metabolomics reveals many novel metabolic markers of heart failure, including pseudouridine and 2-oxoglutarate
Dunn, W. B. And Broadhurst; Deepak, S. M.; Buch, M. H. et al

in Metabolomics (2007), 3(4), 413-426

There is intense interest in the identification of novel biomarkers which improve the diagnosis of heart failure. Serum samples from 52 patients with systolic heart failure (EF< 40% plus signs and ... [more ▼]

There is intense interest in the identification of novel biomarkers which improve the diagnosis of heart failure. Serum samples from 52 patients with systolic heart failure (EF< 40% plus signs and symptoms of failure) and 57 controls were analyzed by gas chromatography - time of flight - mass spectrometry and the raw data reduced to 272 statistically robust metabolite peaks. 38 peaks showed a significant difference between case and control (p <5 × 10-5). Two such metabolites were pseudouridine, a modified nucleotide present in t- and rRNA and a marker of cell turnover, as well as the tricarboxylic acid cycle intermediate 2-oxoglutarate. Furthermore, 3 further new compounds were also excellent discriminators between patients and controls: 2-hydroxy, 2-methylpropanoic acid, erythritol and 2,4,6-trihydroxypyrimidine. Although renal disease may be associated with heart failure, and metabolites associated with renal disease and other markers were also elevated (e.g. urea, creatinine and uric acid), there was no correlation within the patient group between these metabolites and our heart failure biomarkers, indicating that these were indeed biomarkers of heart failure and not renal disease per se. These findings demonstrate the power of data-driven metabolomics approaches to identify such markers of disease. © Springer Science+Business Media, LLC 2007. [less ▲]

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See detailMechanisms of disease: An introduction to clinical sciences
Neyses, Ludwig UL; Buch, MH

in Tomlinson, H; Heagerty, AM; Weetman, AP (Eds.) et al Heart Failure (2007)

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See detail[Cardiology in Great Britain].
Neyses, Ludwig UL

in Deutsche medizinische Wochenschrift (1946) (2006), 131(24), 1409-11

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See detailThe sarcolemmal calcium pump, alpha-1 syntrophin, and neuronal nitric-oxide synthase are parts of a macromolecular protein complex.
Williams, Judith C.; Armesilla, Angel L.; Mohamed, Tamer M. A. et al

in The Journal of biological chemistry (2006), 281(33), 23341-8

The main role of the plasma membrane Ca2+/calmodulin-dependent ATPase (PMCA) is in the removal of Ca2+ from the cytosol. Recently, we and others have suggested a new function for PMCA as a modulator of ... [more ▼]

The main role of the plasma membrane Ca2+/calmodulin-dependent ATPase (PMCA) is in the removal of Ca2+ from the cytosol. Recently, we and others have suggested a new function for PMCA as a modulator of signal transduction pathways. This paper shows the physical interaction between PMCA (isoforms 1 and 4) and alpha-1 syntrophin and proposes a ternary complex of interaction between endogenous PMCA, alpha-1 syntrophin, and NOS-1 in cardiac cells. We have identified that the linker region between the pleckstrin homology 2 (PH2) and the syntrophin unique (SU) domains, corresponding to amino acids 399-447 of alpha-1 syntrophin, is crucial for interaction with PMCA1 and -4. The PH2 and the SU domains alone failed to interact with PMCA. The functionality of the interaction was demonstrated by investigating the inhibition of neuronal nitric-oxide synthase-1 (NOS-1); PMCA is a negative regulator of NOS-1-dependent NO production, and overexpression of alpha-1 syntrophin and PMCA4 resulted in strongly increased inhibition of NO production. Analysis of the expression levels of alpha-1 syntrophin protein in the heart, skeletal muscle, brain, uterus, kidney, or liver of PMCA4-/- mice, did not reveal any differences when compared with those found in the same tissues of wild-type mice. These results suggest that PMCA4 is tethered to the syntrophin complex as a regulator of NOS-1, but its absence does not cause collapse of the complex, contrary to what has been reported for other proteins within the complex, such as dystrophin. In conclusion, the present data demonstrate for the first time the localization of PMCA1b and -4b to the syntrophin.dystrophin complex in the heart and provide a specific molecular mechanism of interaction as well as functionality. [less ▲]

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See detailThe emergence of plasma membrane calcium pump as a novel therapeutic target for heart disease.
Oceandy, Delvac; Buch, Mamta H.; Cartwright, Elizabeth J. et al

in Mini reviews in medicinal chemistry (2006), 6(5), 583-8

The plasma membrane calcium/calmodulin dependent ATPase (PMCA) is a calcium-extruding enzymatic pump important in the control of intracellular calcium concentration. PMCA is the only system for calcium ... [more ▼]

The plasma membrane calcium/calmodulin dependent ATPase (PMCA) is a calcium-extruding enzymatic pump important in the control of intracellular calcium concentration. PMCA is the only system for calcium extrusion in the majority of cells. In excitable cells such as cardiomyocytes however, PMCA has been shown to play only a minor role in calcium homeostasis. In these cells the main mechanism of calcium extrusion is the sodium calcium exchanger. However, increasing evidence points to an important role for PMCA in signal transduction; in particular in the nitric oxide signalling pathway. In this review we will discuss recent advances that support a key role for PMCA in signal transduction and the potential for therapeutic targeting of this molecule in the treatment of cardiac diseases. [less ▲]

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See detailSperm phenotype of mice carrying a gene deletion for the plasma membrane calcium/calmodulin dependent ATPase 4.
Withers, Sarah; Cartwright, Elizabeth J.; Neyses, Ludwig UL

in Molecular and cellular endocrinology (2006), 250(1-2), 93-7

The sarcolemmal calcium pumps (PMCA for plasma membrane calcium/calmodulin dependent ATPase) are a family of 10 transmembrane domain proteins ejecting calcium from the cytosol. They are encoded by four ... [more ▼]

The sarcolemmal calcium pumps (PMCA for plasma membrane calcium/calmodulin dependent ATPase) are a family of 10 transmembrane domain proteins ejecting calcium from the cytosol. They are encoded by four independent genes and at least 21 splice variants have been described. Isoforms 1 and 4 are ubiquitous, whereas isoforms 2 and 3 are confined to neurons and few other cells (e.g. isoform 2 in the myocardium). In non-excitable cells they are thought to be the only calcium ejection systems and their function as governors of calcium balance is hence intuitive since cells cannot survive in a state of calcium overload. Differences in the affinity of the various isoforms for calcium, ATP and calmodulin have been described, but it is unclear whether the pumps have specialized functions over and above their 'housekeeping' role. In particular, in excitable cells, most calcium is ejected by the sodium/calcium exchanger suggesting that the PMCAs may have evolved into a specialized role. Recently, our group has identified a number of specialized functions of the PMCAs, notably a prominent regulatory role of PMCA4 (splice variant b) for neuronal NO synthase as well as for the Ras pathway. In addition, mice carrying a genetic deletion of the PMCA4 gene showed normal female, but completely infertile male animals. This is due to a highly specific defect in sperm motility, which is reduced to zero, with normal fertilization capacity. Overall, a scenario emerges where the plasma membrane calcium pumps fulfil roles far beyond the traditional housekeeping function, notably in cell signaling, sperm motility, and potentially in cell division. Consequently, we are currently exploring their potential as future drug targets for a variety of conditions, as well as their potential use in the development of a male contraception. [less ▲]

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See detailFunctional effects and molecular mechanisms of subtype-selective ERalpha and ERbeta agonists in the cardiovascular system.
Arias-Loza, P. A.; Jazbutyte, V.; Fritzemeier, K. H. et al

in Ernst Schering Foundation symposium proceedings (2006), (1), 87-106

Gender differences in the development of cardiovascular disease suggested for a protective function of estrogens in heart disease. The negative or neutral outcome of clinical trials on hormone replacement ... [more ▼]

Gender differences in the development of cardiovascular disease suggested for a protective function of estrogens in heart disease. The negative or neutral outcome of clinical trials on hormone replacement therapy provides clear evidence that the role of female sex hormones in the cardiovascular system is more complex than previously thought. In particular, the function of estrogens can not be understood without detailed knowledge on the specific function of both estrogen receptor subtypes in the heart and in the vasculature. In here, we review recent studies on subtype selective ERalpha and ERbeta agonists in different animal models of hypertension, cardiac hypertrophy and vascular inflammation. The results indicate that the activation of specific ER subtypes confers specific as well as redundant protective effects in hypertensive heart disease that might ultimately translate into novel treatment options for hypertensive heart disease. [less ▲]

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See detailMedroxyprogesterone acetate but not drospirenone ablates the protective function of 17 beta-estradiol in aldosterone salt-treated rats.
Arias-Loza, Paula Anahi; Hu, Kai; Schafer, Andreas et al

in Hypertension (2006), 48(5), 994-1001

Controversial results obtained from human and animal studies on the prevention of heart disease by estrogens and progestins warrant a better understanding of nuclear hormone receptor function and ... [more ▼]

Controversial results obtained from human and animal studies on the prevention of heart disease by estrogens and progestins warrant a better understanding of nuclear hormone receptor function and interaction. To address this issue and taking into account that effects of synthetic progestins are not only referable to action through the progesterone receptor but may also be mediated by other steroid receptors, we characterized cardiovascular function and inflammatory gene expression in aldosterone salt-treated rats on long-term administration of 17beta-estradiol, medroxyprogesterone acetate, and drospirenone, a new progestogen exhibiting antimineralocorticoid activity. The complex pattern of cardiovascular injury in ovariectomized Wistar rats induced by chronic aldosterone infusion plus a high-salt diet was significantly attenuated in sham-ovariectomized rats and by coadministration of 17beta-estradiol in ovariectomized animals after 8 weeks of continuous treatment. The beneficial role of 17beta-estradiol on blood pressure, cardiac hypertrophy, vascular osteopontin expression, perivascular fibrosis, and impaired NO-dependent relaxation of isolated aortic rings was completely abrogated by coadministration of medroxyprogesterone acetate. In contrast, drospirenone was either neutral or additive to 17beta-estradiol in protecting against aldosterone salt-induced cardiovascular injury and inflammation. The current results support the hypothesis of complex interactions among estrogen, progesterone, glucocorticoid, androgen, and mineralocorticoid receptor signaling in cardiovascular injury and inflammation. Novel progestins, such as drospirenone, confer superior effects compared with medroxyprogesterone acetate in a model of aldosterone-induced heart disease because of its antimineralocorticoid properties. [less ▲]

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See detailAbsence of alpha 7 integrin in dystrophin-deficient mice causes a myopathy similar to Duchenne muscular dystrophy.
Guo, Chun; Willem, Michael; Werner, Alexander et al

in Human molecular genetics (2006), 15(6), 989-98

Both the dystrophin-glycoprotein complex and alpha7beta1 integrin have critical roles in the maintenance of muscle integrity via the provision of mechanical links between muscle fibres and the basement ... [more ▼]

Both the dystrophin-glycoprotein complex and alpha7beta1 integrin have critical roles in the maintenance of muscle integrity via the provision of mechanical links between muscle fibres and the basement membrane. Absence of either dystrophin or alpha7 integrin results in a muscular dystrophy. To clarify the role of alpha7 integrin and dystrophin in muscle development and function, we generated integrin alpha7/dystrophin double-mutant knockout (DKO) mice. Surprisingly, DKO mice survived post-natally and were indistinguishable from wild-type, integrin alpha7-deficient and mdx mice at birth, but died within 24-28 days. Histological analysis revealed a severe muscular dystrophy in DKO mice with endomysial fibrosis and ectopic calcification. Weight loss was correlated with the loss of muscle fibres, indicating that progressive muscle wasting in the double mutant was most likely due to inadequate muscle regeneration. The data further support that premature death of DKO mice is due to cardiac and/or respiratory failure. The integrin alpha7/dystrophin-deficient mouse model, therefore, resembles the pathological changes seen in Duchenne muscular dystrophy and suggests that the different clinical severity of dystrophin deficiency in human and mouse may be due to a fine-tuned difference in expression of dystrophin and integrin alpha7 in both species. Together, these findings indicate an essential role for integrin alpha7 in the maintenance of dystrophin-deficient muscles. [less ▲]

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See detailInhibition of nuclear import of calcineurin prevents myocardial hypertrophy.
Hallhuber, Matthias; Burkard, Natalie; Wu, Rongxue et al

in Circulation Research (2006), 99(6), 626-35

The time that transcription factors remain nuclear is a major determinant for transcriptional activity. It has recently been demonstrated that the phosphatase calcineurin is translocated to the nucleus ... [more ▼]

The time that transcription factors remain nuclear is a major determinant for transcriptional activity. It has recently been demonstrated that the phosphatase calcineurin is translocated to the nucleus with the transcription factor nuclear factor of activated T cells (NF-AT). This study identifies a nuclear localization sequence (NLS) and a nuclear export signal (NES) in the sequence of calcineurin. Furthermore we identified the nuclear cargo protein importinbeta(1) to be responsible for nuclear translocation of calcineurin. Inhibition of the calcineurin/importin interaction by a competitive peptide (KQECKIKYSERV), which mimicked the calcineurin NLS, prevented nuclear entry of calcineurin. A noninhibitory control peptide did not interfere with the calcineurin/importin binding. Using this approach, we were able to prevent the development of myocardial hypertrophy. In angiotensin II-stimulated cardiomyocytes, [(3)H]-leucine incorporation (159%+/-9 versus 111%+/-11; P<0.01) and cell size were suppressed significantly by the NLS peptide compared with a control peptide. The NLS peptide inhibited calcineurin/NF-AT transcriptional activity (227%+/-11 versus 133%+/-8; P<0.01), whereas calcineurin phosphatase activity was unaffected (298%+/-9 versus 270%+/-11; P=NS). We conclude that calcineurin is not only capable of dephosphorylating NF-AT, thus enabling its nuclear import, but the presence of calcineurin in the nucleus is also important for full NF-AT transcriptional activity. [less ▲]

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