Effects of Adenovirus-Mediated Sorcin Overexpression on Excitation-Contraction Coupling in Isolated Rabbit Cardiomyocytes

Seidler, Tim; Miller, S.; Loughrey, Christopher M.; Kania, Astrid; Burow, Annika; Kettlewell, Sarah; Teucher, Nils; Wagner, Stefan; Kögler, Harald; Meyers, Marian B.; Hasenfuß, Gerd; Smith, Godfrey L.

doi:10.1161/01.res.0000081596.90205.e2

Cited by 69 publications

(61 citation statements)

References 36 publications

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“…Both acute viral-based genetic engineering (242,536,810,846) and mouse transgenesis (560) have been used to elucidate the physiological role of sorcin. Gene transfer of sorcin to isolated adult rat (242,536) and mouse (846) cardiac myocytes caused a gain in contractility with a 3.5-fold increase in sorcin expression.…”

Section: Sorcinmentioning

confidence: 99%

“…In contrast, acute overexpression of sorcin in vitro (810) had the opposite effect on cellular function relative to in vivo gene transfer to the rodent myocardium. In rabbit myocytes, sorcin significantly blunted shortening and Ca 2ϩ transient amplitudes (810). Additionally, sorcin overexpression in the rabbit model had reduced SR Ca 2ϩ content and Ca 2ϩ spark amplitude and duration, suggesting that sorcin has a negative effect on EC coupling in rabbit myocytes (810).…”

Section: Sorcinmentioning

confidence: 99%

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Designing Heart Performance by Gene Transfer

Davis¹,

Westfall²,

Townsend³

et al. 2008

Physiological Reviews

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The birth of molecular cardiology can be traced to the development and implementation of high-fidelity genetic approaches for manipulating the heart. Recombinant viral vector-based technology offers a highly effective approach to genetically engineer cardiac muscle in vitro and in vivo. This review highlights discoveries made in cardiac muscle physiology through the use of targeted viral-mediated genetic modification. Here the history of cardiac gene transfer technology and the strengths and limitations of viral and nonviral vectors for gene delivery are reviewed. A comprehensive account is given of the application of gene transfer technology for studying key cardiac muscle targets including Ca2+handling, the sarcomere, the cytoskeleton, and signaling molecules and their posttranslational modifications. The primary objective of this review is to provide a thorough analysis of gene transfer studies for understanding cardiac physiology in health and disease. By comparing results obtained from gene transfer with those obtained from transgenesis and biophysical and biochemical methodologies, this review provides a global view of cardiac structure-function with an eye towards future areas of research. The data presented here serve as a basis for discovery of new therapeutic targets for remediation of acquired and inherited cardiac diseases.

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Section: Sorcinmentioning

confidence: 99%

Section: Sorcinmentioning

confidence: 99%

Designing Heart Performance by Gene Transfer

Davis¹,

Westfall²,

Townsend³

et al. 2008

Physiological Reviews

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show abstract

“…Recombination with pJM17 plasmid and production of replication-deficient adenovirus were performed according to standard procedures as reported previously. 21 Gene transfer with adenovirus encoding ␤-galactosidase (Ad-LacZ) was used as an internal control.…”

Section: Adenoviral Overexpression Of Dgk-in Isolated Rat Neonatal Camentioning

confidence: 99%

Adenovirus-Mediated Overexpression of Diacylglycerol Kinase-ζ Inhibits Endothelin-1–Induced Cardiomyocyte Hypertrophy

et al. 2005

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Background-Diacylglycerol (DAG) is a lipid second messenger that transiently accumulates in cells stimulated by endothelin-1 (ET-1) and other G␣q protein-coupled receptor agonists. Diacylglycerol kinase (DGK) is thought to be an enzyme that controls the cellular levels of DAG by converting it to phosphatidic acid; however, the functional role of DGK has not been examined in cardiomyocytes. Because DGK inactivates DAG, a strong activator of protein kinase C (PKC), we hypothesized that DGK inhibited ET-1-induced activation of a DAG-PKC signaling cascade and subsequent cardiomyocyte hypertrophy. Methods and Results-Real-time reverse transcription-polymerase chain reaction demonstrated a significant increase of DGK-mRNA by ET-1 in cardiomyocytes. To determine the functional role of DGK-, we overexpressed DGK-in cardiomyocytes using a recombinant adenovirus encoding rat DGK-(Ad-DGK). ET-1-induced translocation of PKC-⑀ was blocked by Ad-DGK (PϽ0.01). Ad-DGK also inhibited ET-1-induced activation of extracellular signal-regulated kinase (PϽ0.01). Luciferase reporter assay revealed that ET-1-mediated increase of activator protein-1 (AP1) DNA-binding activity was significantly inhibited by DGK-(PϽ0.01). In cardiomyocytes transfected with DGK-, ET-1 failed to cause gene induction of atrial natriuretic factor, increases in [

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“…Elle exerce une action inhibitrice sur le RyR2. Cet effet est réduit lorsque la sorcine est phosphorylée par la PKA [9,10]. Les protéines évoquées ci-dessus exercent leur action sur le RyR2 par une interaction sur la boucle cytoplasmique.…”

Section: Récepteur De La Ryanodine : Un Complexe Macromoléculaireunclassified

Récepteur de la ryanodine et dysfonctionnement myocardique

2008

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Le couplage excitation-contraction (CEC) est un mécanisme fondamental, caractéristique des cellules contractiles musculaires squelettiques et cardiaques. Il désigne l'ensemble des processus qui assurent la transformation du stimulus électrique (potentiel d'action, PA) en un signal intracellulaire permettant d'activer la contraction des myocytes. La dépolari-sation membranaire conduit à l'ouverture des canaux calciques de type L (aussi appelés récepteurs des dihydropyridines, DHPR) situés essentiellement sur des invaginations membranaires appelées tubules transverses. L'entrée de Ca 2+ qui en résulte est insuffisante pour déclencher la contraction. Elle est cependant suffisante pour activer l'ouverture du canal calcique du réticulum sarcoplasmique (RS), aussi appelé récepteur de la ryanodine, RyR, selon un mécanisme autocatalytique appelé CICR (Ca . Seule la protéine RyR2 est exprimée dans le coeur. C'est un récepteur homotétramérique (565 kDa par sous-unité). L'association quadrangulaire des sousunités dessine un pore central permettant la diffusion des ions Ca 2+ . La structure tridimensionnelle complète de cette macromolécule n'est pas encore connue. On sait cependant que chaque sous-unité est formée d'une partie transmembranaire carboxy-terminale formant le pore du canal et d'une large partie cytoplasmique amino-terminale appelée « pied », impliquée dans la régulation de l'activité du RyR2 par une interaction de type protéine-protéine (Figure 1) [2]. Chacune des sous unités est associée à des protéines régulatrices pour former un complexe macromoléculaire. L'intégrité de leur interaction avec les sous unités du RyR2 joue un rôle déterminant au cours de pathologies cardiaques. Les principales protéines régulatrices caractérisées à ce jour sont décrites ci-dessous.> Le calcium (Ca 2+ ) joue un rôle essentiel dans la contraction cardiaque. Il est stocké dans le réti-culum sarcoplasmique (RS) et libéré massivement à chaque battement cardiaque par le canal calcique du RS : le récepteur de la ryanodine de type 2 (RyR2). Ce canal est un homotétramère dont chacune des sous-unités, formant le pore, est associée à des protéines régulatrices telles que la calstabine 2, la calmoduline, la PKA, la CamKII, ou encore la calsequestrine, pour former un complexe macromoléculaire qui joue un rôle déterminant au cours de pathologies cardiaques. La modification de l'activité du canal ou de l'une de ses protéines régulatrices conduit à des troubles du rythme parfois fatals. La découverte d'une pharmacologie spécifique du RyR2 présente par conséquent un enjeu thérapeutique majeur. <

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Effects of Adenovirus-Mediated Sorcin Overexpression on Excitation-Contraction Coupling in Isolated Rabbit Cardiomyocytes

Cited by 69 publications

References 36 publications

Designing Heart Performance by Gene Transfer

Designing Heart Performance by Gene Transfer

Adenovirus-Mediated Overexpression of Diacylglycerol Kinase-ζ Inhibits Endothelin-1–Induced Cardiomyocyte Hypertrophy

Récepteur de la ryanodine et dysfonctionnement myocardique

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