Cardiovascular Research (CARDIOVASC RES )

Publisher: British Medical Association; British Cardiac Society; European Society of Cardiology, Elsevier

Description

Cardiovascular Research is the International Basic Science Journal of the European Society of Cardiology. The Journal is concerned with both basic and clinical research in the field of cardiovascular physiology and pathophysiology. The Journal welcomes submission of papers both at the molecular, subcellular, cellular, organ and organism level, and of clinically oriented papers offering insight into (patho)physiological mechanisms.

Impact factor 5.81

  • Hide impact factor history
     
    Impact factor
  • 5-year impact
    6.11
  • Cited half-life
    7.00
  • Immediacy index
    1.69
  • Eigenfactor
    0.05
  • Article influence
    1.93
  • Website
    Cardiovascular Research website
  • Other titles
    Cardiovascular research, CVR
  • ISSN
    0008-6363
  • OCLC
    1553351
  • Material type
    Periodical, Internet resource
  • Document type
    Journal / Magazine / Newspaper, Internet Resource

Publisher details

Elsevier

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author can archive a post-print version
  • Conditions
    • Pre-print allowed on any website or open access repository
    • Voluntary deposit by author of authors post-print allowed on authors' personal website, arXiv.org or institutions open scholarly website including Institutional Repository, without embargo, where there is not a policy or mandate
    • Deposit due to Funding Body, Institutional and Governmental policy or mandate only allowed where separate agreement between repository and the publisher exists.
    • Permitted deposit due to Funding Body, Institutional and Governmental policy or mandate, may be required to comply with embargo periods of 12 months to 48 months .
    • Set statement to accompany deposit
    • Published source must be acknowledged
    • Must link to journal home page or articles' DOI
    • Publisher's version/PDF cannot be used
    • Articles in some journals can be made Open Access on payment of additional charge
    • NIH Authors articles will be submitted to PubMed Central after 12 months
    • Publisher last contacted on 18/10/2013
  • Classification
    ​ green

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim Diastolic dysfunction is central to the development of heart failure. To date, there is no effective treatment and only limited understanding of its molecular basis. Recently we showed that the transmembrane proteoglycan syndecan-4 increases in the left ventricle after pressure overload in mice and man; and that syndecan-4 via calcineurin/NFAT promotes myofibroblast differentiation and collagen production upon mechanical stress. The aim of this study was to investigate if syndecan-4 affects collagen cross-linking and myocardial stiffening in the pressure-overloaded heart. Methods and Results Aortic banding (AB) caused concentric hypertrophy and increased passive tension of left ventricular muscle strips, responses that were blunted in syndecan-4−/- mice. Disruption of titin anchoring by salt extraction of actin and myosin filaments revealed that the effect of syndecan-4 on passive tension was due to extracellular matrix remodeling. Expression and activity of the cross-linking enzyme lysyl oxidase (LOX) increased with mechanical stress and was lower in left ventricles and cardiac fibroblasts from syndecan-4−/- mice, which exhibited less collagen cross-linking after AB. Expression of osteopontin (OPN), a matricellular protein able to induce LOX in cardiac fibroblasts, was upregulated in hearts after AB, in mechanically-stressed fibroblasts and in fibroblasts overexpressing syndecan-4, calcineurin or NFAT, but downregulated in fibroblasts lacking syndecan-4 or after NFAT inhibition. Interestingly, the extracellular domain of syndecan-4 facilitated LOX-mediated collagen cross-linking. Conclusions Syndecan-4 exerts a dual role in collagen cross-linking, one involving its cytosolic domain and NFAT signaling leading to collagen, OPN and LOX induction in cardiac fibroblasts; the other involving the extracellular domain promoting LOX-dependent cross-linking. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
    Cardiovascular Research 01/2015;
  • Cardiovascular Research 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims In this work we provide novel insight into the morphology of dissecting abdominal aortic aneurysms in angiotensin II-infused mice. We demonstrate why they exhibit a large variation in shape and, unlike their human counterparts, are located suprarenally rather than infrarenally. Methods and Results We combined synchrotron-based ultra-high resolution ex vivo imaging (phase contrast X-Ray tomographic microscopy) with in vivo imaging (high-frequency ultrasound and contrast-enhanced micro-CT) and image-guided histology. In all mice we observed a tear in the tunica media of the abdominal aorta near the ostium of the celiac artery. Independently we found that, unlike the gradual luminal expansion typical for human aneurysms, the outer diameter increase of angiotensin II-induced dissecting aneurysms in mice was related to one or several intramural hematomas. These were caused by ruptures of the tunica media near the ostium of small suprarenal side branches, which had never been detected by the established small-animal imaging techniques. The tear near the celiac artery led to apparent luminal dilatation, while the intramural hematoma led to a dissection of the tunica adventitia on the left suprarenal side of the aorta. The number of ruptured branches was higher in those aneurysms that extended into the thoracic aorta, which explained the observed variability in aneurysm shape. Conclusions Our results are the first to describe apparent luminal dilatation, suprarenal branch ruptures and intramural hematoma formation in dissecting abdominal aortic aneurysms in mice. Moreover we validate and demonstrate the vast potential of phase contrast X-Ray tomographic microscopy in cardiovascular small animal applications.
    Cardiovascular Research 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: The NLRP3 inflammasome is activated in the ischemic heart promoting caspase-1 activation, inflammation and cell death. Ischemic injury establishes both a priming signal (transcription of inflammasome components) and a trigger (NLRP3 activation). Whether NLRP3 activation, without priming, induces cardiac dysfunction and/or failure is unknown. The aim of the current study was to assess the independent and complementary roles of the priming and the triggering signals in the heart, in absence of ischemia or myocardial injury. We used mice with mutant NLRP3 (constitutively active), NLRP3-A350V, under the control of tamoxifen-driven expression of the Cre recombinase (Nlrp3-A350V/CreT mice). The mice were treated for ten days with tamoxifen before measuring the activity of caspase-1, the effector enzyme in the inflammasome. Tamoxifen treatment induced the inflammasome in the spleen but not in the heart, despite expression of the mutant NLRP3-A350V. The components of the inflammasome was significantly less expressed in the heart compared to the spleen. Subclinical low dose LPS (2 mg/Kg) in Nlrp3-A350V/CreT mice induced the expression of the components of the inflammasome (priming), measured using real-time PCR and Western blot, leading to the formation of an active inflammasome (caspase-1 activation) in the heart and LV systolic dysfunction while low dose LPS was insufficient to induce LV systolic dysfunction in wild type mice (all P<0.01 for mutant vs wild type mice). The signaling pathway governing the inflammasome formation in the heart requires a priming signal in order for an active NLRP3 to induce caspase-1 activation and LV dysfunction. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.
    Cardiovascular Research 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Uncoupling protein 3 (UCP3), located in the mitochondrial inner membrane, is cardioprotective, but its mechanisms of preserving mitochondrial function during ischemia/reperfusion (I/R) are not fully understood. This study investigated whether UCP3 mediates/mimics the cardioprotection of H2O2 preconditioning (H2O2PC) against I/R injury and the downstream pathway that mediates H2O2PC- and UCP3-afforded cardioprotection. H2O2PC at 20 µM for 5 min significantly improved post-ischemic functional recovery, and reduced lactate dehydrogenase (LDH) release and infarct size with concurrently up-regulated UCP3 expressions in perfused rat hearts subjected to global no-flow I/R. These protections were blocked by UCP3 knockdown with short hairpin RNA but mimicked by UCP3 overexpression. Consistently, H2O2PC-attenuated I/R-induced cytosolic and mitochondrial Ca(2+) overload, Ca(2+) transient suppression, mitochondrial ROS burst, and loss of mitochondrial inner membrane potential were reversed by UCP3 knockdown but mimicked by UCP3 overexpression. Moreover, co-immunoprecipitation assay revealed an interaction of UCP3 with the mitochondrial permeability transition pore (mPTP) component, adenine nucleotide translocator (ANT), while the cardioprotection induced by H2O2PC- and UCP3 overexpression in mitochondria, cardiac function, and cell survival was abolished by atractyloside, a mPTP opener binding to ANT, and partially inhibited by a PI3K/Akt inhibitor wortmannin. Furthermore, H2O2PC-up-regulated the phosphorylation of Akt and glycogen synthase kinase 3β were blocked by UCP3 knockdown but mimicked by UCP3 overexpression. UCP3 mediates the cardioprotection of H2O2PC against I/R injury by preserving the mitochondrial function through inhibiting mPTP opening via the interaction with ANT and the PI3K/Akt pathway. Our findings reveal novel mechanisms of UCP3 in the cardioprotection. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.
    Cardiovascular Research 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Contraction of the heart is regulated by electrically-evoked Ca(2+) transients (CaTs). H(+) ions, the end-products of metabolism, modulate CaTs through direct interactions with Ca(2+)-handling proteins and via Na(+)-mediated coupling between acid-extruding proteins (e.g. Na(+)/H(+) exchange, NHE1) and Na(+)/Ca(2+) exchange. Restricted H(+) diffusivity in cytoplasm predisposes pH-sensitive Ca(2+) signaling to becoming non-uniform, but the involvement of readily diffusible intracellular Na(+) ions may provide a means for combatting this. CaTs were imaged in fluo3-loaded rat ventricular myocytes paced at 2 Hz. Cytoplasmic [Na(+)] ([Na(+)]i) was imaged using SBFI. Intracellular acidification by acetate exposure raised diastolic and systolic [Ca(2+)] (also observed with acid-loading by ammonium prepulse or CO2 exposure). The systolic [Ca(2+)] response correlated with a rise in [Na(+)]i and SR Ca(2+)-load, and was blocked by the NHE1 inhibitor cariporide (CO2/HCO3 (-)-free media). Exposure of one half of a myocyte to acetate using dual microperfusion (CO2/HCO3 (-)-free media) raised diastolic [Ca(2+)] locally in the acidified region. Systolic [Ca(2+)] and CaT amplitude increased more uniformly along the length of the cell, but only when NHE1 was functional. Cytoplasmic Na(+) diffusivity (DNa) was measured in quiescent cells, with strophanthidin present to inhibit the Na(+)/K(+) pump. With regional acetate exposure to activate a local NHE-driven Na(+)-influx, DNa was found to be sufficiently fast (680 µm(2)/s) for transmitting the pH-systolic Ca(2+) interaction over long distances. Na(+) ions are rapidly diffusible messengers that expand the spatial scale of cytoplasmic pH-CaT interactions, helping to co-ordinate global Ca(2+) signaling during conditions of intracellular pH non-uniformity. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.
    Cardiovascular Research 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Release of norepinephrine (NE) from sympathetic neurons enhances heart rate (HR) and developed force through activation of β-adrenergic receptors, and this sympathoexcitation is a key risk for the generation of cardiac arrhythmias. Studies of β-adrenergic modulation of cardiac function typically involve the administration of exogenous β-adrenergic receptor agonists to directly elicit global β-adrenergic receptor activation by bypassing the involvement of sympathetic nerve terminals. In this work we use a novel method to activate sympathetic fibers within the myocardium of Langendorff-perfused hearts while measuring changes in electrical and mechanical function. The light activated optogenetic protein channelrhodopsin-2 (ChR2) was expressed in murine catecholaminergic sympathetic neurons. Sympathetic fibers were then photoactivated to examine changes in contractile force, heart rate, and cardiac electrical activity. Incidence of arrhythmia was measured with and without exposure to photoactivation of sympathetic fibers, and hearts were optically mapped to detect changes in action potential durations and conduction velocities. Results demonstrate facilitation of both developed force and heart rate after photo-stimulated release of NE, with increases in contractile force and HR of 34.5±5.5% and 25.0±9.3%, respectively. Photo-stimulation of sympathetic fibers also made hearts more susceptible to arrhythmia, with greater incidence and severity. In addition, optically mapped action potentials displayed a small but significant shortening of the plateau phase (-5.5±1.0 msec) after photostimulation. This study characterizes a powerful and clinically relevant new model for studies of cardiac arrhythmias generated by increasing the activity of sympathetic nerve terminals and the resulting activation of myocyte β-adrenergic receptors. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.
    Cardiovascular Research 12/2014;
  • Cardiovascular Research 12/2014; Epub.
  • Cardiovascular Research 12/2014;
  • Cardiovascular Research 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: The ryanodine receptor (RyR2) is an intracellular Ca(2+) release channel essential for cardiac excitation-contraction coupling. Abnormal RyR2 channel function results in the generation of arrhythmias and sudden cardiac death. The present study was undertaken to investigate the mechanistic basis of RyR2 dysfunction in inherited arrhythmogenic cardiac disease. We present several lines of complementary evidence indicating that the arrhythmia-associated L433P mutation disrupts RyR2 N-terminus self-association. A combination of yeast two-hybrid, co-immunoprecipitation and chemical cross-linking assays collectively demonstrate that a RyR2 N-terminal fragment carrying the L433P mutation displays substantially reduced self-interaction compared to wild-type. Moreover, sucrose density gradient centrifugation reveals that the L433P mutation impairs tetramerization of the full-length channel. [(3)H]Ryanodine binding assays demonstrate that disrupted N-terminal inter-subunit interactions within RyR2(L433P) confer an altered sensitivity to Ca(2+) activation. Calcium imaging of RyR2(L433P)-expressing cells reveals substantially prolonged Ca(2+) transients and reduced Ca(2+) store content indicating defective channel closure. Importantly, dantrolene treatment reverses the L433P mutation-induced impairment and restores channel function. The N-terminus domain constitutes an important structural determinant for the functional oligomerization of RyR2. Our findings are consistent with defective N-terminus self-association as a molecular mechanism underlying RyR2 channel deregulation in inherited arrhythmogenic cardiac disease. Significantly, the therapeutic action of dantrolene may occur via the restoration of normal RyR2 N-terminal inter-subunit interactions. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.
    Cardiovascular Research 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: To examine the role of physiological Akt signaling in pathological hypertrophy through analysis of PHLPP1 (PH domain leucine-rich repeat protein phosphatase) knock-out (KO) mice METHODS AND RESULTS: To investigate the in vivo requirement for "physiological" control of Akt activation in cardiac growth we examined the effect of deleting the Akt phosphatase, PHLPP on the induction of cardiac hypertrophy. Basal Akt phosphorylation increased nearly 2 fold in the cardiomyocytes from PHLPP1 knock-out mice and physiological hypertrophy induced by swimming exercise was accentuated as assessed by increased heart size and myocyte cell area. In contrast, development of pathophysiological hypertrophy induced by pressure overload and assessed by increases in heart size, myocyte cell area and hypertrophic gene expression was attenuated. This attenuation coincided with decreased fibrosis and cell death in the KO mice. Cast molding revealed increased capillary density basally in the knock-out hearts which was further elevated relative to wild-type mouse hearts in response to pressure overload. In vitro studies with isolated myocytes in co-culture also demonstrated that PHLPP1 deletion in cardiomyocytes can enhance endothelial tube formation. Expression of the pro-angiogenic factor VEGF was also elevated basally and accentuated in response to TAC in hearts from KO mice. Our data suggest that enhancing Akt activity by inhibiting its PHLPP1 mediated dephosphorylation promotes processes associated with physiological hypertrophy that may be beneficial in attenuating the development of pathological hypertrophy. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.
    Cardiovascular Research 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims : Stimulation of β-adrenergic receptors (β-AR) increases cAMP production and contributes to the pathogenesis of cardiac hypertrophy and failure through poorly understood mechanisms. We previously demonstrated that Exchange protein directly activated by cAMP 1 (Epac1) induced hypertrophy in primary cardiomyocytes. Among the mechanisms triggered by cardiac stress, autophagy has been highlighted as a protective or harmful response. Here, we investigate whether Epac1 promotes cardiac autophagy and how altered autophagy has an impact on Epac1-induced cardiomyocyte hypertrophy. Methods and Results : We reported that direct stimulation of Epac1 with the agonist, Sp-8-(4-chlorophenylthio)-2′-O-methyl-cAMP (Sp-8-pCPT) promoted autophagy activation in neonatal cardiomyocytes. Stimulation of β-adrenergic receptor (β-AR) with isoprenaline (ISO) mimicked the effect of Epac1 on autophagy markers. Conversely, the induction of autophagy flux following ISO treatment was prevented in cardiomyocytes pre-treated with a selective inhibitor of Epac1, CE3F4. Importantly, we found that Epac1 deletion in mice protected against β-AR induced cardiac remodeling and prevented the induction of autophagy. The signalling mechanisms underlying Epac1-induced autophagy involved a Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ)/AMP-dependent protein kinase (AMPK) pathway. Finally, we provided evidence that pharmacological inhibition of autophagy using 3-methyladenine (3-MA) or down-regulation of autophagy-related protein 5 (Atg5) significantly potentiated Epac1-promoted cardiomyocyte hypertrophy. Conclusion : Altogether, these findings demonstrate that autophagy is an adaptive response to antagonize Epac1-promoted cardiomyocyte hypertrophy.
    Cardiovascular Research 11/2014;
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    ABSTRACT: S100A1, a 10-kDa, Ca(2+) -binding protein is expressed in endothelial cells (EC) and binds eNOS. Its absence is associated with impaired production of nitric oxide (NO) and mild systemic hypertension. As endothelial dysfunction contributes to clinical and experimental pulmonary hypertension (PH), we investigated the impact of deleting S100A1 in mice, on pulmonary hemodynamics, endothelial function, NO production, associated signalling pathways and apoptosis.
    Cardiovascular Research 11/2014;
  • Cardiovascular Research 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: The MEK5/Erk5 pathway mediates beneficial effects of laminar flow, a major physiological factor preventing vascular dysfunction. Forced Erk5 activation induces a protective phenotype in endothelial cell (EC) that is associated with a dramatically decreased migration capacity of those cells. Transcriptional profiling identified the Krüppel-like transcription factors KLF2 and KLF4 as central mediators of Erk5-dependent gene expression. However, their downstream role regarding migration is unclear and relevant secondary effectors remain elusive. Here, we further investigated the mechanism underlying Erk5-dependent migration arrest in ECs.
    Cardiovascular Research 11/2014;