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  1. Article: Regulation of GPCR signaling in hypertension.

    Brinks, Henriette L / Eckhart, Andrea D

    Biochimica et biophysica acta

    2010  Volume 1802, Issue 12, Page(s) 1268–1275

    Abstract: Hypertension represents a complex, multifactorial disease and contributes to the major causes of morbidity and mortality in industrialized countries: ischemic and hypertensive heart disease, stroke, peripheral atherosclerosis and renal failure. Current ... ...

    Abstract Hypertension represents a complex, multifactorial disease and contributes to the major causes of morbidity and mortality in industrialized countries: ischemic and hypertensive heart disease, stroke, peripheral atherosclerosis and renal failure. Current pharmacological therapy of essential hypertension focuses on the regulation of vascular resistance by inhibition of hormones such as catecholamines and angiotensin II, blocking them from receptor activation. Interaction of G-protein coupled receptor kinases (GRKs) and regulator of G-protein signaling (RGS) proteins with activated G-protein coupled receptors (GPCRs) effect the phosphorylation state of the receptor leading to desensitization and can profoundly impair signaling. Defects in GPCR regulation via these modulators have severe consequences affecting GPCR-stimulated biological responses in pathological situations such as hypertension, since they fine-tune and balance the major transmitters of vessel constriction versus dilatation, thus representing valuable new targets for anti-hypertensive therapeutic strategies. Elevated levels of GRKs are associated with human hypertensive disease and are relevant modulators of blood pressure in animal models of hypertension. This implies therapeutic perspective in a disease that has a prevalence of 65million in the United States while being directly correlated with occurrence of major adverse cardiac and vascular events. Therefore, therapeutic approaches using the inhibition of GRKs to regulate GPCRs are intriguing novel targets for treatment of hypertension and heart failure.
    MeSH term(s) Angiotensin II/genetics ; Angiotensin II/metabolism ; Animals ; Antihypertensive Agents/therapeutic use ; Blood Pressure/genetics ; Catecholamines/genetics ; Catecholamines/metabolism ; Disease Models, Animal ; GTP-Binding Proteins/genetics ; GTP-Binding Proteins/metabolism ; Humans ; Hypertension/drug therapy ; Hypertension/epidemiology ; Hypertension/genetics ; Hypertension/metabolism ; Prevalence ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor Protein-Tyrosine Kinases/metabolism ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction ; United States/epidemiology ; Vasoconstriction/genetics ; Vasodilation/genetics
    Chemical Substances Antihypertensive Agents ; Catecholamines ; Receptors, G-Protein-Coupled ; Angiotensin II (11128-99-7) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; GTP-Binding Proteins (EC 3.6.1.-)
    Language English
    Publishing date 2010-01-11
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 60-7
    ISSN 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbadis.2010.01.005
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  2. Article ; Online: Transapical access closure: the TA PLUG device.

    Brinks, Henriette / Nietlispach, Fabian / Göber, Volkhard / Englberger, Lars / Wenaweser, Peter / Meier, Bernhard / Carrel, Thierry / Huber, Christoph

    Interactive cardiovascular and thoracic surgery

    2013  Volume 17, Issue 5, Page(s) 806–9; discussion 809–10

    Abstract: Objectives: Percutaneous closure of the transapical (TA) access site for large-calibre devices is an unsolved issue. We report the first experimental data on the TA PLUG device for true-percutaneous closure following large apical access for ... ...

    Abstract Objectives: Percutaneous closure of the transapical (TA) access site for large-calibre devices is an unsolved issue. We report the first experimental data on the TA PLUG device for true-percutaneous closure following large apical access for transcatheter aortic valve implantation.
    Methods: The TA PLUG, a self-sealing full-core closure device, was implanted in an acute animal study in six pigs (60.2 ± 0.7 kg). All the pigs received 100 IU/kg of heparin. The targeted activated clotting time was left to normalize spontaneously. After accessing the left ventricular apex with a 39 French introducer, the closure plug device was delivered with a 33 French over-the-wire system under fluoroscopic guidance into the apex. Time to full haemostasis as well as rate of bleeding was recorded. Self-anchoring properties were assessed by haemodynamic push stress under adrenalin challenge. An additional feasibility study was conducted in four pigs (58.4 ± 1.1 kg) with full surgical exposure of the apex, and assessed device anchoring by pull-force measurements with 0.5 Newton (N) increments. All the animals were electively sacrified. Post-mortem analysis of the heart was performed and the renal embolic index assessed.
    Results: Of six apical closure devices, five were correctly inserted and fully deployed at the first attempt. One became blocked in the delivery system and was placed successfully at the second attempt. In all the animals, complete haemostasis was immediate and no leak was recorded during the 5-h observation period. Neither leak nor any device dislodgement was observed under haemodynamic push stress with repeated left ventricular peak pressure of up to 220 mmHg. In the feasibility study assessing pull-stressing, device migration occurred at a force of 3.3 ± 0.5 N corresponding to 247.5 mmHg. Post-mortem analyses confirmed full expansion of all devices at the intended target. No macroscopic damage was identified at the surrounding myocardium. The renal embolic index was zero.
    Conclusions: True-percutaneous left ventricular apex closure following large access is feasible with the self-sealing TA PLUG. The device allows for immediate haemostasis and a reliable anchoring in the acute animal setting. This is the first report of a true-percutaneous closure for large-calibre transcatheter aortic valve implantation access.
    MeSH term(s) Animals ; Cardiac Catheterization/adverse effects ; Cardiac Catheterization/instrumentation ; Cardiac Catheters ; Equipment Design ; Feasibility Studies ; Foreign-Body Migration/etiology ; Heart Valve Prosthesis Implantation/adverse effects ; Heart Valve Prosthesis Implantation/instrumentation ; Heart Valve Prosthesis Implantation/methods ; Hemodynamics ; Hemorrhage/etiology ; Hemorrhage/physiopathology ; Hemorrhage/prevention & control ; Hemostatic Techniques/instrumentation ; Materials Testing ; Models, Animal ; Punctures ; Stress, Mechanical ; Swine ; Time Factors
    Language English
    Publishing date 2013-07-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2095298-3
    ISSN 1569-9285 ; 1569-9293
    ISSN (online) 1569-9285
    ISSN 1569-9293
    DOI 10.1093/icvts/ivt309
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  3. Article ; Online: Control of ventricular unloading using an electrocardiogram-synchronized Thoratec paracorporeal ventricular assist device.

    Amacher, Raffael / Weber, Alberto / Brinks, Henriette / Axiak, Shannon / Ferreira, Antonio / Guzzella, Lino / Carrel, Thierry / Antaki, James / Vandenberghe, Stijn

    The Journal of thoracic and cardiovascular surgery

    2013  Volume 146, Issue 3, Page(s) 710–717

    Abstract: Objective: Current pulsatile ventricular assist devices operate asynchronous with the left ventricle in fixed-rate or fill-to-empty modes because electrocardiogram-triggered modes have been abandoned. We hypothesize that varying the ejection delay in ... ...

    Abstract Objective: Current pulsatile ventricular assist devices operate asynchronous with the left ventricle in fixed-rate or fill-to-empty modes because electrocardiogram-triggered modes have been abandoned. We hypothesize that varying the ejection delay in the synchronized mode yields more precise control of hemodynamics and left ventricular loading. This allows for a refined management that may be clinically beneficial.
    Methods: Eight sheep received a Thoratec paracorporeal ventricular assist device (Thoratec Corp, Pleasanton, Calif) via ventriculo-aortic cannulation. Left ventricular pressure and volume, aortic pressure, pulmonary flow, pump chamber pressure, and pump inflow and outflow were recorded. The pump was driven by a clinical pneumatic drive unit (Medos Medizintechnik AG, Stolberg, Germany) synchronously with the native R-wave. The start of pump ejection was delayed between 0% and 100% of the cardiac period in 10% increments. For each of these delays, hemodynamic variables were compared with baseline data using paired t tests.
    Results: The location of the minimum of stroke work was observed at a delay of 10% (soon after aortic valve opening), resulting in a median of 43% reduction in stroke work compared with baseline. Maximum stroke work occurred at a median delay of 70% with a median stroke work increase of 11% above baseline. Left ventricular volume unloading expressed by end-diastolic volume was most pronounced for copulsation (delay 0%).
    Conclusions: The timing of pump ejection in synchronized mode yields control over left ventricular energetics and can be a method to achieve gradual reloading of a recoverable left ventricle. The traditionally suggested counterpulsation is not optimal in ventriculo-aortic cannulation when maximum unloading is desired.
    MeSH term(s) Animals ; Aorta/physiopathology ; Arterial Pressure ; Disease Models, Animal ; Electrocardiography ; Heart Rate ; Heart-Assist Devices ; Prosthesis Design ; Pulmonary Circulation ; Pulsatile Flow ; Regional Blood Flow ; Sheep ; Stroke Volume ; Time Factors ; Ventricular Dysfunction, Left/physiopathology ; Ventricular Dysfunction, Left/therapy ; Ventricular Function, Left ; Ventricular Pressure
    Language English
    Publishing date 2013-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3104-5
    ISSN 1097-685X ; 0022-5223
    ISSN (online) 1097-685X
    ISSN 0022-5223
    DOI 10.1016/j.jtcvs.2012.12.048
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  4. Article ; Online: Inhibition of Fas-associated death domain-containing protein (FADD) protects against myocardial ischemia/reperfusion injury in a heart failure mouse model.

    Fan, Qian / Huang, Zheng M / Boucher, Matthieu / Shang, Xiying / Zuo, Lin / Brinks, Henriette / Lau, Wayne Bond / Zhang, Jianke / Chuprun, J Kurt / Gao, Erhe

    PloS one

    2013  Volume 8, Issue 9, Page(s) e73537

    Abstract: Aim: As technological interventions treating acute myocardial infarction (MI) improve, post-ischemic heart failure increasingly threatens patient health. The aim of the current study was to test whether FADD could be a potential target of gene therapy ... ...

    Abstract Aim: As technological interventions treating acute myocardial infarction (MI) improve, post-ischemic heart failure increasingly threatens patient health. The aim of the current study was to test whether FADD could be a potential target of gene therapy in the treatment of heart failure.
    Methods: Cardiomyocyte-specific FADD knockout mice along with non-transgenic littermates (NLC) were subjected to 30 minutes myocardial ischemia followed by 7 days of reperfusion or 6 weeks of permanent myocardial ischemia via the ligation of left main descending coronary artery. Cardiac function were evaluated by echocardiography and left ventricular (LV) catheterization and cardiomyocyte death was measured by Evans blue-TTC staining, TUNEL staining, and caspase-3, -8, and -9 activities. In vitro, H9C2 cells transfected with ether scramble siRNA or FADD siRNA were stressed with chelerythrin for 30 min and cleaved caspase-3 was assessed.
    Results: FADD expression was significantly decreased in FADD knockout mice compared to NLC. Ischemia/reperfusion (I/R) upregulated FADD expression in NLC mice, but not in FADD knockout mice at the early time. FADD deletion significantly attenuated I/R-induced cardiac dysfunction, decreased myocardial necrosis, and inhibited cardiomyocyte apoptosis. Furthermore, in 6 weeks long term permanent ischemia model, FADD deletion significantly reduced the infarct size (from 41.20 ± 3.90% in NLC to 26.83 ± 4.17% in FADD deletion), attenuated myocardial remodeling, improved cardiac function and improved survival. In vitro, FADD knockdown significantly reduced chelerythrin-induced the level of cleaved caspase-3.
    Conclusion: Taken together, our results suggest FADD plays a critical role in post-ischemic heart failure. Inhibition of FADD retards heart failure progression. Our data supports the further investigation of FADD as a potential target for genetic manipulation in the treatment of heart failure.
    MeSH term(s) Animals ; Apoptosis/drug effects ; Benzophenanthridines/pharmacology ; Caspase 3/genetics ; Caspase 3/metabolism ; Caspase 8/genetics ; Caspase 8/metabolism ; Caspase 9/genetics ; Caspase 9/metabolism ; Cells, Cultured ; Coronary Vessels/surgery ; Disease Models, Animal ; Fas-Associated Death Domain Protein/antagonists & inhibitors ; Fas-Associated Death Domain Protein/deficiency ; Fas-Associated Death Domain Protein/genetics ; Gene Expression Regulation ; Heart Failure/genetics ; Heart Failure/metabolism ; Heart Failure/pathology ; Male ; Mice ; Mice, Knockout ; Myocardial Reperfusion Injury/genetics ; Myocardial Reperfusion Injury/metabolism ; Myocardial Reperfusion Injury/pathology ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Proteolysis ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Severity of Illness Index ; Ventricular Dysfunction, Left/genetics ; Ventricular Dysfunction, Left/metabolism ; Ventricular Dysfunction, Left/pathology
    Chemical Substances Benzophenanthridines ; Fadd protein, mouse ; Fas-Associated Death Domain Protein ; RNA, Small Interfering ; chelerythrine (E3B045W6X0) ; Casp3 protein, mouse (EC 3.4.22.-) ; Casp9 protein, mouse (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Caspase 8 (EC 3.4.22.-) ; Caspase 9 (EC 3.4.22.-)
    Language English
    Publishing date 2013-09-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0073537
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  5. Article ; Online: Myocardial Ablation of G Protein-Coupled Receptor Kinase 2 (GRK2) Decreases Ischemia/Reperfusion Injury through an Anti-Intrinsic Apoptotic Pathway.

    Fan, Qian / Chen, Mai / Zuo, Lin / Shang, Xiying / Huang, Maggie Z / Ciccarelli, Michele / Raake, Philip / Brinks, Henriette / Chuprun, Kurt J / Dorn, Gerald W / Koch, Walter J / Gao, Erhe

    PloS one

    2013  Volume 8, Issue 6, Page(s) e66234

    Abstract: Studies from our lab have shown that decreasing myocardial G protein-coupled receptor kinase 2 (GRK2) activity and expression can prevent heart failure progression after myocardial infarction. Since GRK2 appears to also act as a pro-death kinase in ... ...

    Abstract Studies from our lab have shown that decreasing myocardial G protein-coupled receptor kinase 2 (GRK2) activity and expression can prevent heart failure progression after myocardial infarction. Since GRK2 appears to also act as a pro-death kinase in myocytes, we investigated the effect of cardiomyocyte-specific GRK2 ablation on the acute response to cardiac ischemia/reperfusion (I/R) injury. To do this we utilized two independent lines of GRK2 knockout (KO) mice where the GRK2 gene was deleted in only cardiomyocytes either constitutively at birth or in an inducible manner that occurred in adult mice prior to I/R. These GRK2 KO mice and appropriate control mice were subjected to a sham procedure or 30 min of myocardial ischemia via coronary artery ligation followed by 24 hrs reperfusion. Echocardiography and hemodynamic measurements showed significantly improved post-I/R cardiac function in both GRK2 KO lines, which correlated with smaller infarct sizes in GRK2 KO mice compared to controls. Moreover, there was significantly less TUNEL positive myocytes, less caspase-3, and -9 but not caspase-8 activities in GRK2 KO mice compared to control mice after I/R injury. Of note, we found that lowering cardiac GRK2 expression was associated with significantly lower cytosolic cytochrome C levels in both lines of GRK2 KO mice after I/R compared to corresponding control animals. Mechanistically, the anti-apoptotic effects of lowering GRK2 expression were accompanied by increased levels of Bcl-2, Bcl-xl, and increased activation of Akt after I/R injury. These findings were reproduced in vitro in cultured cardiomyocytes and GRK2 mRNA silencing. Therefore, lowering GRK2 expression in cardiomyocytes limits I/R-induced injury and improves post-ischemia recovery by decreasing myocyte apoptosis at least partially via Akt/Bcl-2 mediated mitochondrial protection and implicates mitochondrial-dependent actions, solidifying GRK2 as a pro-death kinase in the heart.
    MeSH term(s) Animals ; Apoptosis ; Cytochromes c/metabolism ; G-Protein-Coupled Receptor Kinase 2/antagonists & inhibitors ; G-Protein-Coupled Receptor Kinase 2/genetics ; G-Protein-Coupled Receptor Kinase 2/metabolism ; Hemodynamics/drug effects ; Isoproterenol/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocardial Infarction/metabolism ; Myocardial Infarction/pathology ; Myocardial Reperfusion Injury/metabolism ; Myocardial Reperfusion Injury/pathology ; Myocardium/enzymology ; Myocardium/pathology ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/metabolism ; Oxidative Stress ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA Interference ; Up-Regulation ; bcl-X Protein/metabolism
    Chemical Substances Proto-Oncogene Proteins c-bcl-2 ; bcl-X Protein ; Cytochromes c (9007-43-6) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; G-Protein-Coupled Receptor Kinase 2 (EC 2.7.11.16) ; Isoproterenol (L628TT009W)
    Language English
    Publishing date 2013-06-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0066234
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  6. Article ; Online: Clinical outcomes of patients with severe aortic stenosis at increased surgical risk according to treatment modality.

    Wenaweser, Peter / Pilgrim, Thomas / Kadner, Alexander / Huber, Christoph / Stortecky, Stefan / Buellesfeld, Lutz / Khattab, Ahmed A / Meuli, Fabienne / Roth, Nadja / Eberle, Balthasar / Erdös, Gabor / Brinks, Henriette / Kalesan, Bindu / Meier, Bernhard / Jüni, Peter / Carrel, Thierry / Windecker, Stephan

    Journal of the American College of Cardiology

    2011  Volume 58, Issue 21, Page(s) 2151–2162

    Abstract: Objectives: The aim of this study was to assess the role of transcatheter aortic valve implantation (TAVI) compared with medical treatment (MT) and surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis (AS) at increased ... ...

    Abstract Objectives: The aim of this study was to assess the role of transcatheter aortic valve implantation (TAVI) compared with medical treatment (MT) and surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis (AS) at increased surgical risk.
    Background: Elderly patients with comorbidities are at considerable risk for SAVR.
    Methods: Since July 2007, 442 patients with severe AS (age: 81.7 ± 6.0 years, mean logistic European System for Cardiac Operative Risk Evaluation: 22.3 ± 14.6%) underwent treatment allocation to MT (n = 78), SAVR (n = 107), or TAVI (n = 257) on the basis of a comprehensive evaluation protocol as part of a prospective registry.
    Results: Baseline clinical characteristics were similar among patients allocated to MT and TAVI, whereas patients allocated to SAVR were younger (p < 0.001) and had a lower predicted peri-operative risk (p < 0.001). Unadjusted rates of all-cause mortality at 30 months were lower for SAVR (22.4%) and TAVI (22.6%) compared with MT (61.5%, p < 0.001). Adjusted hazard ratios for death were 0.51 (95% confidence interval: 0.30 to 0.87) for SAVR compared with MT and 0.38 (95% confidence interval: 0.25 to 0.58) for TAVI compared with MT. Medical treatment (<0.001), older age (>80 years, p = 0.01), peripheral vascular disease (<0.001), and atrial fibrillation (p = 0.04) were significantly associated with all-cause mortality at 30 months in the multivariate analysis. At 1 year, more patients undergoing SAVR (92.3%) or TAVI (93.2%) had New York Heart Association functional class I/II as compared with patients with MT (70.8%, p = 0.003).
    Conclusions: Among patients with severe AS with increased surgical risk, SAVR and TAVI improve survival and symptoms compared with MT. Clinical outcomes of TAVI and SAVR seem similar among carefully selected patients with severe symptomatic AS at increased risk.
    MeSH term(s) Aged ; Aged, 80 and over ; Aortic Valve Stenosis/diagnosis ; Aortic Valve Stenosis/mortality ; Aortic Valve Stenosis/surgery ; Atrial Fibrillation/epidemiology ; Atrial Fibrillation/etiology ; Cardiac Catheterization/adverse effects ; Female ; Follow-Up Studies ; Heart Valve Prosthesis/adverse effects ; Hospital Mortality/trends ; Humans ; Male ; Prospective Studies ; Severity of Illness Index ; Switzerland/epidemiology ; Treatment Outcome
    Language English
    Publishing date 2011-11-15
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Randomized Controlled Trial
    ZDB-ID 605507-2
    ISSN 1558-3597 ; 0735-1097
    ISSN (online) 1558-3597
    ISSN 0735-1097
    DOI 10.1016/j.jacc.2011.05.063
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  7. Article ; Online: Cardiac G-protein-coupled receptor kinase 2 ablation induces a novel Ca2+ handling phenotype resistant to adverse alterations and remodeling after myocardial infarction.

    Raake, Philip W / Zhang, Xiaoying / Vinge, Leif E / Brinks, Henriette / Gao, Erhe / Jaleel, Naser / Li, Yingxin / Tang, Mingxin / Most, Patrick / Dorn, Gerald W / Houser, Steven R / Katus, Hugo A / Chen, Xiongwen / Koch, Walter J

    Circulation

    2012  Volume 125, Issue 17, Page(s) 2108–2118

    Abstract: ... by increased L-type Ca(2+) channel currents. After β-adrenergic stimulation, GRK2KO myocytes revealed ... significant increases in contractility and Ca(2+) transients, which were not mediated through cardiac L-type ... because of better-maintained L-type Ca(2+) channel current density and no increase in sodium-Ca(2+) exchanger ...

    Abstract Background: G-protein-coupled receptor kinase 2 (GRK2) is a primary regulator of β-adrenergic signaling in the heart. G-protein-coupled receptor kinase 2 ablation impedes heart failure development, but elucidation of the cellular mechanisms has not been achieved, and such elucidation is the aim of this study.
    Methods and results: Myocyte contractility, Ca(2+) handling and excitation-contraction coupling were studied in isolated cardiomyocytes from wild-type and GRK2 knockout (GRK2KO) mice without (sham) or with myocardial infarction (MI). In cardiac myocytes isolated from unstressed wild-type and GRK2KO hearts, myocyte contractions and Ca(2+) transients were similar, but GRK2KO myocytes had lower sarcoplasmic reticulum (SR) Ca(2+) content because of increased sodium-Ca(2+) exchanger activity and inhibited SR Ca(2+) ATPase by local protein kinase A-mediated activation of phosphodiesterase 4 resulting in hypophosphorylated phospholamban. This Ca(2+) handling phenotype is explained by a higher fractional SR Ca(2+) release induced by increased L-type Ca(2+) channel currents. After β-adrenergic stimulation, GRK2KO myocytes revealed significant increases in contractility and Ca(2+) transients, which were not mediated through cardiac L-type Ca(2+) channels but through an increased SR Ca(2+). Interestingly, post-MI GRK2KO mice showed better cardiac function than post-MI control mice, which is explained by an improved Ca(2+) handling phenotype. The SR Ca(2+) content was better maintained in post-MI GRK2KO myocytes than in post-MI control myocytes because of better-maintained L-type Ca(2+) channel current density and no increase in sodium-Ca(2+) exchanger in GRK2KO myocytes. An L-type Ca(2+) channel blocker, verapamil, reversed some beneficial effects of GRK2KO.
    Conclusions: These data argue for novel differential regulation of L-type Ca(2+) channel currents and SR load by GRK2. G-protein-coupled receptor kinase 2 ablation represents a novel beneficial Ca(2+) handling phenotype resisting adverse remodeling after MI.
    MeSH term(s) Adrenergic beta-Agonists/pharmacology ; Animals ; Calcium/metabolism ; Calcium Channel Blockers/pharmacology ; Calcium Channels, L-Type/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Excitation Contraction Coupling/physiology ; G-Protein-Coupled Receptor Kinase 2/deficiency ; G-Protein-Coupled Receptor Kinase 2/genetics ; G-Protein-Coupled Receptor Kinase 2/physiology ; Heart Failure/etiology ; Heart Failure/prevention & control ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocardial Contraction ; Myocardial Infarction/complications ; Myocardial Infarction/enzymology ; Myocytes, Cardiac/metabolism ; Phenotype ; Protein Structure, Tertiary ; Receptors, Adrenergic, beta/physiology ; Sarcoplasmic Reticulum/metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; Sodium-Calcium Exchanger/metabolism ; Ventricular Remodeling/physiology ; Verapamil/pharmacology
    Chemical Substances Adrenergic beta-Agonists ; Calcium Channel Blockers ; Calcium Channels, L-Type ; Receptors, Adrenergic, beta ; Sodium-Calcium Exchanger ; Verapamil (CJ0O37KU29) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; GRK2 protein, mouse (EC 2.7.11.15) ; G-Protein-Coupled Receptor Kinase 2 (EC 2.7.11.16) ; Sarcoplasmic Reticulum Calcium-Transporting ATPases (EC 3.6.3.8) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2012-04-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80099-5
    ISSN 1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
    ISSN (online) 1524-4539
    ISSN 0009-7322 ; 0069-4193 ; 0065-8499
    DOI 10.1161/CIRCULATIONAHA.111.044255
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  8. Article ; Online: The repulsive guidance molecule RGMa is involved in the formation of afferent connections in the dentate gyrus.

    Brinks, Henriette / Conrad, Sabine / Vogt, Johannes / Oldekamp, Judit / Sierra, Ana / Deitinghoff, Lutz / Bechmann, Ingo / Alvarez-Bolado, Gonzalo / Heimrich, Bernd / Monnier, Philippe P / Mueller, Bernhard K / Skutella, Thomas

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2002  Volume 24, Issue 15, Page(s) 3862–3869

    Abstract: In the developing dentate gyrus, afferent fiber projections terminate in distinct laminas. This relies on an accurately regulated spatiotemporal network of guidance molecules. Here, we have analyzed the functional role of the glycosylphosphatidylinositol ...

    Abstract In the developing dentate gyrus, afferent fiber projections terminate in distinct laminas. This relies on an accurately regulated spatiotemporal network of guidance molecules. Here, we have analyzed the functional role of the glycosylphosphatidylinositol (GPI)-anchored repulsive guidance molecule RGMa. In situ hybridization in embryonic and postnatal brain showed expression of RGMa in the cornu ammonis and hilus of the hippocampus. In the dentate gyrus, RGM immunostaining was confined to the inner molecular layer, whereas the outer molecular layers targeted by entorhinal fibers remained free. To test the repulsive capacity of RGMa, different setups were used: the stripe and explant outgrowth assays with recombinant RGMa, and entorhino-hippocampal cocultures incubated either with a neutralizing RGMa antibody (Ab) or with the GPI anchor-digesting drug phosphatidylinositol-specific phospholipase C. Entorhinal axons were clearly repelled by RGMa in the stripe and outgrowth assays. After disrupting the RGMa function, the specific laminar termination pattern in entorhino-hippocampal cocultures was lost, and entorhinal axons entered inappropriate hippocampal areas. Our data indicate an important role of RGMa for the layer-specific termination of the perforant pathway as a repulsive signal that compels entorhinal fibers to stay in their correct target zone.
    MeSH term(s) Afferent Pathways/cytology ; Afferent Pathways/embryology ; Afferent Pathways/metabolism ; Animals ; Animals, Newborn ; Antibodies/pharmacology ; Cell Differentiation/physiology ; Cells, Cultured ; Chick Embryo ; Dentate Gyrus/cytology ; Dentate Gyrus/embryology ; Dentate Gyrus/metabolism ; Entorhinal Cortex/cytology ; Entorhinal Cortex/embryology ; Entorhinal Cortex/physiology ; GPI-Linked Proteins ; Hippocampus/cytology ; Hippocampus/embryology ; Hippocampus/physiology ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Ligands ; Mice ; Nerve Tissue Proteins/antagonists & inhibitors ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/physiology ; Neurites/physiology ; Transfection
    Chemical Substances Antibodies ; GPI-Linked Proteins ; Ligands ; Nerve Tissue Proteins ; Rgma protein, mouse
    Language English
    Publishing date 2002-11-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.5296-03.2004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through G(βγ)-mediated L-type calcium current disinhibition.

    Völkers, Mirko / Weidenhammer, Christian / Herzog, Nicole / Qiu, Gang / Spaich, Kristin / Wegner, Frederic V / Peppel, Karsten / Müller, Oliver J / Schinkel, Stefanie / Rabinowitz, Joseph E / Hippe, Hans-Jorg / Brinks, Henriette / Katus, Hugo A / Koch, Walter J / Eckhart, Andrea D / Friedrich, Oliver / Most, Patrick

    Circulation research

    2010  Volume 108, Issue 1, Page(s) 27–39

    Abstract: ... we demonstrate that βARKct enhances the cardiac L-type Ca²(+) channel (LCC) current (I(Ca)) both in NCs and FCs ...

    Abstract Rationale: The G(βγ)-sequestering peptide β-adrenergic receptor kinase (βARK)ct derived from the G-protein-coupled receptor kinase (GRK)2 carboxyl terminus has emerged as a promising target for gene-based heart failure therapy. Enhanced downstream cAMP signaling has been proposed as the underlying mechanism for increased β-adrenergic receptor (βAR) responsiveness. However, molecular targets mediating improved cardiac contractile performance by βARKct and its impact on G(βγ)-mediated signaling have yet to be fully elucidated.
    Objective: We sought to identify G(βγ)-regulated targets and signaling mechanisms conveying βARKct-mediated enhanced βAR responsiveness in normal (NC) and failing (FC) adult rat ventricular cardiomyocytes.
    Methods and results: Assessing viral-based βARKct gene delivery with electrophysiological techniques, analysis of contractile performance, subcellular Ca²(+) handling, and site-specific protein phosphorylation, we demonstrate that βARKct enhances the cardiac L-type Ca²(+) channel (LCC) current (I(Ca)) both in NCs and FCs on βAR stimulation. Mechanistically, βARKct augments I(Ca) by preventing enhanced inhibitory interaction between the α1-LCC subunit (Cav1.2α) and liberated G(βγ) subunits downstream of activated βARs. Despite improved βAR contractile responsiveness, βARKct neither increased nor restored cAMP-dependent protein kinase (PKA) and calmodulin-dependent kinase II signaling including unchanged protein kinase (PK)Cε, extracellular signal-regulated kinase (ERK)1/2, Akt, ERK5, and p38 activation both in NCs and FCs. Accordingly, although βARKct significantly increases I(Ca) and Ca²(+) transients, being susceptible to suppression by recombinant G(βγ) protein and use-dependent LCC blocker, βARKct-expressing cardiomyocytes exhibit equal basal and βAR-stimulated sarcoplasmic reticulum Ca²(+) load, spontaneous diastolic Ca²(+) leakage, and survival rates and were less susceptible to field-stimulated Ca²(+) waves compared with controls.
    Conclusion: Our study identifies a G(βγ)-dependent signaling pathway attenuating cardiomyocyte I(Ca) on βAR as molecular target for the G(βγ)-sequestering peptide βARKct. Targeted interruption of this inhibitory signaling pathway by βARKct confers improved βAR contractile responsiveness through increased I(Ca) without enhancing regular or restoring abnormal cAMP-signaling. βARKct-mediated improvement of I(Ca) rendered cardiomyocytes neither susceptible to βAR-induced damage nor arrhythmogenic sarcoplasmic reticulum Ca²(+) leakage.
    MeSH term(s) Animals ; Calcium/metabolism ; Calcium Channels, L-Type/genetics ; Calcium Channels, L-Type/metabolism ; Cardiotonic Agents/metabolism ; Cell Survival/genetics ; G-Protein-Coupled Receptor Kinase 2 ; GTP-Binding Protein beta Subunits/genetics ; GTP-Binding Protein beta Subunits/metabolism ; GTP-Binding Protein gamma Subunits/genetics ; GTP-Binding Protein gamma Subunits/metabolism ; Genetic Therapy/methods ; Heart Failure/genetics ; Heart Failure/metabolism ; Heart Failure/therapy ; Heart Ventricles/metabolism ; MAP Kinase Signaling System/genetics ; Myocardial Contraction/genetics ; Myocytes, Cardiac/metabolism ; Peptides/genetics ; Peptides/metabolism ; Protein Kinases/genetics ; Protein Kinases/metabolism ; Rats ; Sarcoplasmic Reticulum/genetics ; Sarcoplasmic Reticulum/metabolism
    Chemical Substances Cacna1c protein, rat ; Calcium Channels, L-Type ; Cardiotonic Agents ; GTP-Binding Protein beta Subunits ; GTP-Binding Protein gamma Subunits ; Peptides ; Protein Kinases (EC 2.7.-) ; Grk2 protein, rat (EC 2.7.11.15) ; G-Protein-Coupled Receptor Kinase 2 (EC 2.7.11.16) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2010-11-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80100-8
    ISSN 1524-4571 ; 0009-7330 ; 0931-6876
    ISSN (online) 1524-4571
    ISSN 0009-7330 ; 0931-6876
    DOI 10.1161/CIRCRESAHA.110.225201
    Database MEDical Literature Analysis and Retrieval System OnLINE

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