8 条评论 发表在“Circulation Research 2008年12月5日”上

1. 匿名 说：

   2010年02月24日于1:06 上午

   Reviews
   Autophagy in Load-Induced Heart Disease
   Beverly A. Rothermel and Joseph A. Hill
   Circ Res. 2008;103:1363-1369, doi:10.1161/CIRCRESAHA.108.186551
   Abstract
   The heart is a highly plastic organ capable of remodeling in response to changes in physiological or pathological demand. For example, when workload increases, compensatory hypertrophic growth of individual cardiomyocytes occurs to increase cardiac output. Sustained stress, however, such as that occurring with hypertension or following myocardial infarction, triggers changes in energy metabolism and sarcomeric protein composition, loss of cardiomyocytes, ventricular dilation, reduced pump function, and ultimately heart failure. It has been known for some time that autophagy is active in cardiomyocytes, occurring at increased levels in disease. Now, with recent advances in our understanding of molecular mechanisms governing autophagy, the potential contributions of cardiomyocyte autophagy to ventricular remodeling and disease pathogenesis are being explored. As part of this work, several recent studies have focused on autophagy in heart disease elicited by changes in hemodynamic load. Pressure overload stress elicits a robust autophagic response in cardiomyocytes that is maladaptive, contributing to disease progression. In this context, load-induced aggregation of intracellular proteins is a proximal event triggering autophagic clearance mechanisms. These findings in the setting of pressure overload contrast with protein aggregation occurring in a model of protein chaperone malfunction, where activation of autophagy is beneficial, antagonizing disease progression. Here, we review recent studies of cardiomyocyte autophagy in load-induced disease and address molecular mechanisms and unanswered questions.
   Key Words:
   autophagy • cardiac hypertrophy • heart failure • hypertrophy • signal transduction
   http://g.zhubajie.com/urllink.php?id=3395811wrdaihlgv4wfvh82
   Notch and Vascular Smooth Muscle Cell Phenotype
   David Morrow, Shaunta Guha, Catherine Sweeney, Yvonne Birney, Tony Walshe, Colm O’Brien, Dermot Walls, Eileen M. Redmond, and Paul A. Cahill
   Circ Res. 2008;103:1370-1382, doi:10.1161/CIRCRESAHA.108.187534
   Abstract
   The Notch signaling pathway is critical for cell fate determination during embryonic development, including many aspects of vascular development. An emerging paradigm suggests that the Notch gene regulatory network is often recapitulated in the context of phenotypic modulation of vascular smooth muscle cells (VSMC), vascular remodeling, and repair in adult vascular disease following injury. Notch ligand receptor interactions lead to cleavage of receptor, translocation of the intracellular receptor (Notch IC), activation of transcriptional CBF-1/RBP-J–dependent and –independent pathways, and transduction of downstream Notch target gene expression. Hereditary mutations of Notch components are associated with congenital defects of the cardiovascular system in humans such as Alagille syndrome and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Recent loss- or gain-of-function studies have provided insight into novel Notch-mediated CBF-1/RBP-J–dependent and –independent signaling and cross-regulation to other molecules that may play a critical role in VSMC phenotypic switching. Notch receptors are critical for controlling VSMC differentiation and dictating the phenotypic response following vascular injury through interaction with a triad of transcription factors that act synergistically to regulate VSMC differentiation. This review focuses on the role of Notch receptor ligand interactions in dictating VSMC behavior and phenotype and presents recent findings on the molecular interactions between the Notch components and VSMC-specific genes to further understand the function of Notch signaling in vascular tissue and disease.
   Key Words:
   Notch • vascular phenotype • differentiation • disease
   http://g.zhubajie.com/urllink.php?id=3395813j1tn8c6g05mewsir
2. 匿名 说：

   2010年02月24日于1:06 上午

   Molecular Medicine
   S-Endoglin Expression Is Induced in Senescent Endothelial Cells and Contributes to Vascular Pathology
   Francisco J. Blanco, María T. Grande, Carmen Langa, Barbara Oujo, Soraya Velasco, Alicia Rodriguez-Barbero, Eduardo Perez-Gomez, Miguel Quintanilla, Jose M. López-No***, and Carmelo Bernabeu
   Circ Res. 2008;103:1383-1392; published online before print October 30 2008, doi:10.1161/CIRCRESAHA.108.176552
   Abstract
   Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-β receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-β receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-β type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-β–responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-β1 administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology.
   Key Words:
   endothelial cells • hypertension • TGF-β receptors • aging • endoglin
   http://g.zhubajie.com/urllink.php?id=3395822p3h3fph0h06nkzan
   Platelet-Derived Growth Factor Receptor β Signaling Is Required for Efficient Epicardial Cell Migration and Development of Two Distinct Coronary Vascular Smooth Muscle Cell Populations
   Amy M. Mellgren, Christopher L. Smith, Gregory S. Olsen, Banu Eskiocak, Bin Zhou, Michelle N. Kazi, Fernanda R. Ruiz, William T. Pu, and Michelle D. Tallquist
   Circ Res. 2008;103:1393-1401; published online before print October 23 2008, doi:10.1161/CIRCRESAHA.108.176768
   Abstract
   The epicardium plays an essential role in coronary artery formation and myocardial development, but signals controlling the development and differentiation of this tissue are not well understood. To investigate the role of platelet-derived growth factor receptor (PDGFR)β in development of epicardial-derived vascular smooth muscle cells (VSMCs), we examined PDGFRβ–/– and PDGFRβ epicardial mutant hearts. We found that PDGFRβ–/– hearts failed to form dominant coronary vessels on the ventral heart surface, had a thinned myocardium, and completely lacked coronary VSMCs (cVSMCs). This constellation of defects was consistent with a primary defect in the epicardium. To verify that these defects were specific to epicardial derivatives, we generated mice with an epicardial deletion of PDGFRβ that resulted in reduced cVSMCs distal to the aorta. The regional absence of cVSMCs suggested that cVSMCs could arise from 2 sources, epicardial and nonepicardial, and that both were dependent on PDGFRβ. In the absence of PDGFRβ signaling, epicardial cells adopted an irregular actin cytoskeleton, leading to aberrant migration of epicardial cells into the myocardium in vivo. In addition, PDGF receptor stimulation promoted epicardial cell migration, and PDGFRβ-driven phosphoinositide 3′-kinase signaling was critical for this process. Our data demonstrate that PDGFRβ is required for the formation of 2 distinct cVSMC populations and that loss of PDGFRβ-PI3K signaling disrupts epicardial cell migration.
   Key Words:
   epicardium • PDGF • coronary vascular smooth muscle • migration • PI3K
   http://g.zhubajie.com/urllink.php?id=3395826dzjr88syqyenn5id
   Toll-Like Receptor 2 Mediates Apolipoprotein CIII–Induced Monocyte Activation
   Akio Kawakami, Mizuko Osaka, Masanori Aikawa, Satoshi Uematsu, Shizuo Akira, Peter Libby, Kentaro Shimokado, Frank M. Sacks, and Masayuki Yoshida
   Circ Res. 2008;103:1402-1409; published online before print October 30 2008, doi:10.1161/CIRCRESAHA.108.178426
   Abstract
   Apolipoprotein (apo)CIII predicts risk for coronary heart disease. We recently reported that apoCIII directly activates human monocytes. Recent evidence indicates that toll-like receptor (TLR)2 can contribute to atherogenesis through transduction of inflammatory signals. Here, we tested the hypothesis that apoCIII activates human monocytoid THP-1 cells through TLR2. ApoCIII induced the association of TLR2 with myeloid differentiation factor 88, activated nuclear factor (NF)-B in THP-1 cells, and increased their adhesion to human umbilical vein endothelial cells (HUVECs). Anti-TLR2 blocking antibody, but not anti-TLR4 blocking antibody or isotype-matched IgG, inhibited these processes (P<0.05). ApoCIII bound with high affinity to human recombinant TLR2 protein and showed a significantly higher (P<0.05) and saturable binding to 293 cells overexpressing human TLR2 than to parental 293 cells with no endogenous TLR2. Overexpression of TLR2 in 293 cells augmented apoCIII-induced NF-B activation and β1 integrin expression, processes inhibited by anti-apoCIII antibody as well as anti-TLR2 antibody. Exposure of peripheral blood monocytes isolated from C57BL/6 (wild-type) mice to apoCIII activated their NF-B and increased their adhesiveness to HUVECs. In contrast, apoCIII did not activate monocytes from TLR2-deficient mice. Finally, intravenous administration to C57BL/6 mice of apoCIII-rich very-low-density lipoprotein (VLDL), but not of apoCIII-deficient VLDL, activated monocytes and increased their adhesiveness to HUVECs, processes attenuated by anti-TLR2 or anti-apoCIII antibody. ApoCIII-rich VLDL did not activate monocytes from TLR2-deficient mice. In conclusion, apoCIII activated monocytes at least partly through a TLR2-dependent pathway. The present study identifies a novel mechanism for proinflammatory and proatherogenic effects of apoCIII and a role for TLR2 in atherosclerosis induced by atherogenic lipoproteins.
   Key Words:
   apolipoprotein • atherosclerosis • inflammation • monocyte • Toll-like receptor
   http://g.zhubajie.com/urllink.php?id=3395827589hbnz5p7jws1ae
   Ecto-5′ Nucleotidase (CD73)-Mediated Adenosine Generation and Signaling in Murine Cardiac Allograft Vasculopathy
   Tomomi Hasegawa, Diane Bouïs, Hui Liao, Scott H. Visovatti, and David J. Pinsky
   Circ Res. 2008;103:1410-1421; published online before print November 13 2008, doi:10.1161/CIRCRESAHA.108.180059
   Abstract
   Ecto-5′-nucleotidase (CD73) catalyzes the terminal phosphohydrolysis of 5′-adenosine monophosphate and is widely expressed on endothelial cells where it regulates barrier function. Because it is also expressed on lymphocytes, we hypothesized that it modulates vascular immune regulation under homeostatic conditions and dysregulation under stress conditions such as cardiac allotransplantation. In a heterotopic cardiac allotransplantation model, CD73 deficiency in either donors or recipients resulted in decreased graft survival and the development of cardiac allograft vasculopathy, suggesting a contribution of CD73 on both graft-resident and circulating cells in vasculopathy pathogenesis. Vascular perturbations incited by lack of CD73 included loss of graft barrier function and diminished graft expression of the A2B adenosine receptor (A2BAR), with a concordant exacerbation of the acute inflammatory and immune responses. The importance of CD73 in modulating endothelial–lymphocyte interaction was further demonstrated in allomismatched in vitro coculture experiments. Either genetic deletion or pharmacological blockade of CD73 increased transendothelial lymphocyte migration and inflammatory responses, suggesting that CD73 plays a critical role to suppress transendothelial leukocyte trafficking through its enzymatic activity. In addition, antagonism of A2BAR caused a significant increase in vascular leakage, and agonism of A2BAR resulted in marked prolongation of graft survival and suppression of cardiac allograft vasculopathy development. These data suggest a new paradigm in which phosphohydrolysis of adenosine monophosphate by CD73 on graft-resident or circulating cells diminishes transendothelial leukocyte trafficking and mitigates inflammatory and immune sequelae of cardiac transplantation via the A2BAR.
   Key Words:
   ecto-5′-nucleotidase • adenosine receptor • cardiac allograft vasculopathy
   http://g.zhubajie.com/urllink.php?id=3395840jpquxd02v0dzdy7m
   Cardiac Neural Crest Expression of Hand2 Regulates Outflow and Second Heart Field Development
   Yuka Morikawa and Peter Cserjesi
   Circ Res. 2008;103:1422-1429; published online before print November 13 2008, doi:10.1161/CIRCRESAHA.108.180083
   Abstract
   The cardiac neural crest (cNC) lineage plays key roles in heart development by directly contributing to heart structures and regulating development of other heart lineages. The basic helix–loop–helix factor Hand2 regulates development of cardiovascular structures and NC-derived tissues including those that contribute to face and peripheral nervous system. Although Hand2 is expressed in cNC, its role has not been examined because of an early embryonic lethality when Hand2 is deleted in the NC lineage. We find that the lethality is attributable to loss of norepinephrine synthesis that can be overcome by activating adrenergic receptors. In rescued embryos, loss of Hand2 in the NC lineage leads to the misalignment of the outflow tract and aortic arch arteries. Defects include pulmonary stenosis, interrupted aortic artery, retroesophageal right subclavian artery, and ventricular septum defect, which resemble congenital heart defects attributed to defects in the NC. Hand2 functions in part by regulating signaling from the cNC to other cardiac lineages but not by regulating migration or survival of the cNC. Loss of Hand2 in NC also uncovered a novel role for the cNC in regulating proliferation and differentiation of the second heart field–derived myocardium that persists late into development. These results show that the cNC functions as a major signaling center for heart development and Hand2 plays a pivotal role in regulating both cell-autonomous and -nonautonomous functions of the cNC.
   Key Words:
   neural crest • Hand2 • hypertrabeculation
   http://g.zhubajie.com/urllink.php?id=3395846d3c9knzdc6j6f6y0
   MEKK3 Initiates Transforming Growth Factor β2–Dependent Epithelial-to-Mesenchymal Transition During Endocardial Cushion Morphogenesis
   Mark V. Stevens, Derrick M. Broka, Patti Parker, Elisa Rogowitz, Richard R. Vaillancourt, and Todd D. Camenisch
   Circ Res. 2008;103:1430-1440; published online before print November 13 2008, doi:10.1161/CIRCRESAHA.108.180752
   Abstract
   Congenital heart defects occur at a rate of 5% and are the most prevalent birth defects. A better understanding of the complex signaling networks regulating heart development is necessary to improve repair strategies for congenital heart defects. The mitogen-activated protein 3 kinase (MEKK3) is important to early embryogenesis, but developmental processes affected by MEKK3 during heart morphogenesis have not been fully examined. We identify MEKK3 as a critical signaling molecule during endocardial cushion development. We report the detection of MEKK3 transcripts to embryonic hearts before, during, and after cardiac cushion cells have executed epithelial-to-mesenchymal transition (EMT). MEKK3 is observed to endocardial cells of the cardiac cushions with a diminishing gradient of expression into the cushions. These observations suggest that MEKK3 may function during production of cushion mesenchyme as required for valvular development and septation of the heart. We used a kinase inactive form of MEKK3 (MEKK3KI) in an in vitro assay that recapitulates in vivo EMT and show that MEKK3KI attenuates mesenchyme formation. Conversely, constitutively active MEKK3 (ca-MEKK3) triggers mesenchyme production in ventricular endocardium, a tissue that does not normally undergo EMT. MEKK3-driven mesenchyme production is further substantiated by increased expression of EMT-relevant genes, including TGFβ2, Has2, and periostin. Furthermore, we show that MEKK3 stimulates EMT via a TGFβ2-dependent mechanism. Thus, the activity of MEKK3 is sufficient for developmental EMT in the heart. This knowledge provides a basis to understand how MEKK3 integrates signaling cascades activating endocardial cushion EMT.
   Key Words:
   epithelial-to-mesenchymal transition • MEKK3 • TGFβ2 • endocardial cushions • heart
   http://g.zhubajie.com/urllink.php?id=3395860kxjzdkssa76h3u35
   P53 Impairs Endothelium-Dependent Vasomotor Function Through Transcriptional Upregulation of P66shc
   Cuk-Seong Kim, Saet-Byel Jung, Asma Naqvi, Timothy A. Hoffman, Jeremy DeRicco, Tohru Yamamori, Marsha P. Cole, Byeong-Hwa Jeon, and Kaikobad Irani
   Circ Res. 2008;103:1441-1450; published online before print November 6 2008, doi:10.1161/CIRCRESAHA.108.181644
   Abstract
   The transcription factor, p53, and the adaptor protein, p66shc, both play essential roles in promoting oxidative stress in the vascular system. However, the relationship between the two in the context of endothelium-dependent vascular tone is unknown. Here, we report a novel, evolutionarily conserved, p53-mediated transcriptional mechanism that regulates p66shc expression and identify p53 as an important determinant of endothelium-dependent vasomotor function. We provide evidence of a p53 response element in the promoter of p66shc and show that angiotensin II-induced upregulation of p66shc in endothelial cells is dependent on p53. In addition, we demonstrate that downregulation of p66shc expression, as well as inhibition of p53 function in mice, mitigates angiotensin II-induced impairment of endothelium-dependent vasorelaxation, decrease in bioavailable nitric oxide, and hypertension. These findings reveal a novel p53-dependent transcriptional mechanism for the regulation of p66shc expression that is operative in the vascular endothelium and suggest that this mechanism is important in impairing endothelium-dependent vascular relaxation.
   Key Words:
   tumor suppressor p53 • p66shc • angiotensin II • endothelial dysfunction
   http://g.zhubajie.com/urllink.php?id=3395864la1gkk10ah4bavoq
3. 匿名 说：

   2010年02月24日于1:06 上午

   Cellular Biology
   Long QT Syndrome–Associated Mutations in KCNQ1 and KCNE1 Subunits Disrupt Normal Endosomal Recycling of IKs Channels
   Guiscard Seebohm, Nathalie Strutz-Seebohm, Oana N. Ureche, Ulrike Henrion, Ravshan Baltaev, Andreas F. Mack, Ganna Korniychuk, Katja Steinke, Daniel Tapken, Arne Pfeufer, Stefan Kääb, Cecilia Bucci, Bernard Attali, Jean Merot, Jeremy M. Tavare, Uta C. Hoppe, Michael C. Sanguinetti, and Florian Lang
   Circ Res. 2008;103:1451-1457; published online before print November 13 2008, doi:10.1161/CIRCRESAHA.108.177360
   Abstract
   Physical and emotional stress is accompanied by release of stress hormones such as the glucocorticoid cortisol. This hormone upregulates the serum- and glucocorticoid-inducible kinase (SGK)1, which in turn stimulates IKs, a slow delayed rectifier potassium current that mediates cardiac action potential repolarization. Mutations in IKs channel (KCNQ1, KvLQT1, Kv7.1) or β (KCNE1, IsK, minK) subunits cause long QT syndrome (LQTS), an inherited cardiac arrhythmia associated with increased risk of sudden death. Together with the GTPases RAB5 and RAB11, SGK1 facilitates membrane recycling of KCNQ1 channels. Here, we show altered SGK1-dependent regulation of LQTS-associated mutant IKs channels. Whereas some mutant KCNQ1 channels had reduced basal activity but were still activated by SGK1, currents mediated by KCNQ1(Y111C) or KCNQ1(L114P) were paradoxically reduced by SGK1. Heteromeric channels coassembled of wild-type KCNQ1 and the LQTS-associated KCNE1(D76N) mutant were similarly downregulated by SGK1 because of a disrupted RAB11-dependent recycling. Mutagenesis experiments indicate that stimulation of IKs channels by SGK1 depends on residues H73, N75, D76, and P77 in KCNE1. Identification of the IKs recycling pathway and its modulation by stress-stimulated SGK1 provides novel mechanistic insight into potentially fatal cardiac arrhythmias triggered by physical or psychological stress.
   Key Words:
   kinase • trafficking • PIKfyve • LQT • stress
   http://g.zhubajie.com/urllink.php?id=3395893cor7i4ar6pp8e7ua
   Differential Structure of Atrial and Ventricular KATP: Atrial KATP Channels Require SUR1
   Thomas P. Flagg, Harley T. Kurata, Ricard Masia, George Caputa, Mark A. Magnuson, David J. Lefer, William A. Coetzee, and Colin G. Nichols
   Circ Res. 2008;103:1458-1465; published online before print October 30 2008, doi:10.1161/CIRCRESAHA.108.178186
   Abstract
   The isoform-specific structure of the ATP-sensitive potassium (KATP) channel endows it with differential fundamental properties, including physiological activation and pharmacology. Numerous studies have convincingly demonstrated that the pore-forming Kir6.2 (KCNJ11) and regulatory SUR2A (ABCC9) subunits are essential elements of the sarcolemmal KATP channel in cardiac ventricular myocytes. Using a novel antibody directed against the COOH terminus of SUR1 (ABCC8), we show that this KATP subunit is also expressed in mouse myocardium and is the dominant SUR isoform in the atrium. This suggests differential sarcolemmal KATP composition in atria and ventricles, and, to test this, KATP currents were measured in isolated atrial and ventricular myocytes from wild-type and SUR1–/– animals. KATP conductance is essentially abolished in SUR1–/– atrial myocytes but is normal in SUR1–/– ventricular myocytes. Furthermore, pharmacological properties of wild-type atrial KATP match closely the properties of heterologously expressed SUR1/Kir6.2 channels, whereas ventricular KATP properties match those of heterologously expressed SUR2A/Kir6.2 channels. Collectively, the data demonstrate a previously unappreciated KATP channel heterogeneity: SUR1 is an essential component of atrial, but not ventricular, KATP channels. Differential molecular make-up of the 2 channels underlies differential pharmacology, with important implications when considering sulfonylurea therapy or dissecting the role of cardiac KATP pharmacologically, as well as for understanding of the role of diazoxide in preconditioning.
   Key Words:
   diazoxide • sarcolemmal • mitochondrial • ABCC8 • ABCC9
   http://g.zhubajie.com/urllink.php?id=3395901muadt164c5ov46mu
   Redox Modification of Ryanodine Receptors Contributes to Sarcoplasmic Reticulum Ca2+ Leak in Chronic Heart Failure
   Dmitry Terentyev, Inna Györke, Andriy E. Belevych, Radmila Terentyeva, Arun Sridhar, Yoshinori Nishijima, Esperanza Carcache de Blanco, Savita Khanna, Chandan K. Sen, Arturo J. Cardounel, Cynthia A. Carnes, and Sandor Györke
   Circ Res. 2008;103:1466-1472; published online before print November 13 2008, doi:10.1161/CIRCRESAHA.108.184457
   Abstract
   Abnormal cardiac ryanodine receptor (RyR2) function is recognized as an important factor in the pathogenesis of heart failure (HF). However, the specific molecular causes underlying RyR2 defects in HF remain poorly understood. In the present study, we used a canine model of chronic HF to test the hypothesis that the HF-related alterations in RyR2 function are caused by posttranslational modification by reactive oxygen species generated in the failing heart. Experimental approaches included imaging of cytosolic ([Ca2+]c) and sarcoplasmic reticulum (SR) luminal Ca2+ ([Ca2+]SR) in isolated intact and permeabilized ventricular myocytes and single RyR2 channel recording using the planar lipid bilayer technique. The ratio of reduced to oxidized glutathione, as well as the level of free thiols on RyR2 decreased markedly in failing versus control hearts consistent with increased oxidative stress in HF. RyR2-mediated SR Ca2+ leak was significantly enhanced in permeabilized myocytes, resulting in reduced [Ca2+]SR in HF compared to control cells. Both SR Ca2+ leak and [Ca2+]SR were partially normalized by treating HF myocytes with reducing agents. Conversely, oxidizing agents accelerated SR Ca2+ leak and decreased [Ca2+]SR in cells from normal hearts. Moreover, exposure to antioxidants significantly improved intracellular Ca2+-handling parameters in intact HF myocytes. Single RyR2 channel activity was significantly higher in HF versus control because of increased sensitivity to activation by luminal Ca2+ and was partially normalized by reducing agents through restoring luminal Ca2+ sensitivity oxidation of control RyR2s enhanced their luminal Ca2+ sensitivity, thus reproducing the HF phenotype. These findings suggest that redox modification contributes to abnormal function of RyR2s in HF, presenting a potential therapeutic target for treating HF.
   Key Words:
   ryanodine receptor • heart failure • disulfide oxidation • Ca2+-induced Ca2+ release
   http://g.zhubajie.com/urllink.php?id=3395908ftyqrve5a5nhfu0z
4. 匿名 说：

   2010年02月24日于1:06 上午

   Integrative Physiology
   B-Crystallin Suppresses Pressure Overload Cardiac Hypertrophy
   Asangi R.K. Kumarapeli, Huabo Su, Wei Huang, Mingxin Tang, Hanqiao Zheng, Kathleen M. Horak, Manxiang Li, and Xuejun Wang
   Circ Res. 2008;103:1473-1482; published online before print October 30 2008, doi:10.1161/CIRCRESAHA.108.180117
   Abstract
   B-Crystallin (CryA is the most abundant small heat shock protein (HSP) constitutively expressed in cardiomyocytes. Gain- and loss-of-function studies demonstrated that CryAB can protect against myocardial ischemia/reperfusion injury. However, the role of CryAB or any HSPs in cardiac responses to mechanical overload is unknown. This study addresses this issue. Nontransgenic mice and mice with cardiomyocyte-restricted transgenic overexpression of CryAB or with germ-line ablation of the CryAB/HSPB2 genes were subjected to transverse aortic constriction or sham surgery. Two weeks later, cardiac responses were analyzed by fetal gene expression profiling, cardiac function analyses, and morphometry. Comparison among the 3 sham surgery groups reveals that CryAB overexpression is benign, whereas the knockout is detrimental to the heart as reflected by cardiac hypertrophy and malfunction at 10 weeks of age. Compared to nontransgenic mice, transgenic mouse hearts showed significantly reduced NFAT transactivation and attenuated cardiac hypertrophic responses to transverse aortic constriction but unchanged cardiac function, whereas NFAT transactivation was significantly increased in cardiac and skeletal muscle of the knockout mice at baseline, and they developed cardiac insufficiency at 2 weeks after transverse aortic constriction. CryAB overexpression in cultured neonatal rat cardiomyocytes significantly attenuated adrenergic stimulation-induced NFAT transactivation and hypertrophic growth. We conclude that CryAB suppresses cardiac hypertrophic responses likely through attenuating NFAT signaling and that CryAB and/or HSPB2 are essential for normal cardiac function.
   Key Words:
   heat shock proteins • hypertrophy • nuclear factors of activated T cells (NFAT) • myocyte-enriched calcineurin interacting protein-1 (MCIP1) • fetal genes
   http://g.zhubajie.com/urllink.php?id=3395916irn7mme5vg0smo8x
   Homozygous Missense N629D hERG (KCNH2) Potassium Channel Mutation Causes Developmental Defects in the Right Ventricle and Its Outflow Tract and Embryonic Lethality
   Guo Qi Teng, Xian Zhao, James P. Lees-Miller, F. Russell Quinn, Pin Li, Derrick E. Rancourt, Barry London, James C. Cross, and Henry J. Duff
   Circ Res. 2008;103:1483-1491; published online before print October 23 2008, doi:10.1161/CIRCRESAHA.108.177055
   Abstract
   Loss-of-function mutations in the human ERG1 potassium channel (hERG1) frequently underlie the long QT2 (LQT2) syndrome. The role of the ERG potassium channel in cardiac development was elaborated in an in vivo model of a homozygous, loss-of-function LQT2 syndrome mutation. The hERG N629D mutation was introduced into the orthologous mouse gene, mERG, by homologous recombination in mouse embryonic stem cells. Intact homozygous embryos showed abrupt cessation of the heart beat. N629D/N629D embryos die in utero by embryonic day 11.5. Their developmental defects include altered looping architecture, poorly developed bulbus cordis, and distorted aortic sac and branchial arches. N629D/N629D myocytes from embryonic day 9.5 embryos manifested complete loss of IKr function, depolarized resting potential, prolonged action potential duration (LQT), failure to repolarize, and propensity to oscillatory arrhythmias. N629D/N629D myocytes manifest calcium oscillations and increased sarcoplasmic reticulum Ca+2 content. Although the N629D/N629D protein is synthesized, it is mainly located intracellularly, whereas +/+ mERG protein is mainly in plasmalemma. N629D/N629D embryos show robust apoptosis in craniofacial regions, particularly in the first branchial arch and, to a lesser extent, in the cardiac outflow tract. Because deletion of Hand2 produces apoptosis, in similar regions and with a similar final developmental phenotype, Hand2 expression was evaluated. Robust decrease in Hand2 expression was observed in the secondary heart field in N629D/N629D embryos. In conclusion, loss of IKr function in N629D/N629D cardiovascular system leads to defects in cardiac ontogeny in the first branchial arch, outflow tract, and the right ventricle.
   Key Words:
   KCNH2 (hERG) • knock-in mouse • embryo developmental defect
   http://g.zhubajie.com/urllink.php?id=339592297xrk6f3ooo4ki6l
5. 匿名 说：

   2010年02月24日于1:06 上午

   Reports
   O-Linked GlcNAc Modification of Cardiac Myofilament Proteins: A Novel Regulator of Myocardial Contractile Function
   Genaro A. Ramirez-Correa, Wenhai Jin, Zihao Wang, Xin Zhong, Wei Dong Gao, Wagner B. Dias, Cecilia Vecoli, Gerald W. Hart, and Anne M. Murphy
   Circ Res. 2008;103:1354-1358; published online before print November 6 2008, doi:10.1161/CIRCRESAHA.108.184978
   Abstract
   In addition to O-phosphorylation, O-linked modifications of serine and threonine by β-N-acetyl-D-glucosamine (GlcNAc) may regulate muscle contractile function. This study assessed the potential role of O-GlcNAcylation in cardiac muscle contractile activation. To identify specific sites of O-GlcNAcylation in cardiac myofilament proteins, a recently developed methodology based on GalNAz-biotin labeling followed by dithiothreitol replacement and light chromatography/tandem mass spectrometry site mapping was adopted. Thirty-two O-GlcNAcylated peptides from cardiac myofilaments were identified on cardiac myosin heavy chain, actin, myosin light chains, and troponin I. To assess the potential physiological role of the GlcNAc, force–[Ca2+] relationships were studied in skinned rat trabeculae. Exposure to GlcNAc significantly decreased calcium sensitivity (pCa50), whereas maximal force (Fmax) and Hill coefficient were not modified. Using a pan-specific O-GlcNAc antibody, it was determined that acute exposure of myofilaments to GlcNAc induced a significant increase in actin O-GlcNAcylation. This study provides the first identification of O-GlcNAcylation sites in cardiac myofilament proteins and demonstrates their potential role in regulating myocardial contractile function.
   Key Words:
   O-GlcNAc • myofilaments • posttranslational modifications • cardiac contractility • diabetic cardiomyopathy
   http://g.zhubajie.com/urllink.php?id=3395939ohm8i8jgthyryyh3
   Loss of Bmx Nonreceptor Tyrosine Kinase Prevents Pressure Overload–Induced Cardiac Hypertrophy
   Scherise A. Mitchell-Jordan, Tanja Holopainen, Shuxun Ren, Sujing Wang, Sarah Warburton, Michael J. Zhang, Kari Alitalo, Yibin Wang, and Thomas M. Vondriska
   Circ Res. 2008;103:1359-1362; published online before print November 6 2008, doi:10.1161/CIRCRESAHA.108.186577
   Abstract
   Bmx nonreceptor tyrosine kinase has an established role in endothelial and lymphocyte signaling; however, its role in the heart is unknown. To determine whether Bmx participates in cardiac growth, we subjected mice deficient in the molecule (Bmx knockout mice) to transverse aortic constriction (TAC). In comparison with wild-type mice, which progressively developed massive hypertrophy following TAC, Bmx knockout mice were resistant to TAC-induced cardiac growth at the organ and cell level. Loss of Bmx preserved cardiac ejection fraction and decreased mortality following TAC. These findings are the first to demonstrate a necessary role for the Tec family of tyrosine kinases in the heart and reveal a novel regulator (Bmx) of pressure overload–induced hypertrophic growth.
   Key Words:
   tyrosine kinase • cardiac hypertrophy • signal transduction
   http://g.zhubajie.com/urllink.php?id=3395947pxv122oxa14v23lh
6. 匿名 说：

   2010年02月24日于1:06 上午

   Late-Breaking Basic Science Abstracts
   Late-Breaking Basic Science Abstracts: From the American Heart Association Scientific Sessions 2008, New Orleans, Louisiana, November 8–12, 2008
   Circ Res. 2008;103:1493-1501; published online before print November 6 2008, doi:10.1161/CIRCRESAHA.108.100001
   http://g.zhubajie.com/urllink.php?id=3395953c973katb2tcvbtw0
7. 匿名 说：

   2010年02月24日于1:06 上午

   自制本期电子书（PDF，带书签）下载（20M）
   http://g.zhubajie.com/urllink.php?id=3396039r8q5racqwka7h3mx
8. 匿名 说：

   2010年02月24日于1:06 上午

   感谢11600954站友对进展翻译所做的工作，同时期待更多的站友关注国外期刊及翻译！