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Sarcoplasmic Reticulum Adenosine Triphosphatase Overexpression in the L-type Ca2+ Channel Mouse Results in Cardiomyopathy and Ca2+-Induced Arrhythmogenesis

Background: Overexpression of the L-type voltage-dependent calcium channel α1C-subunit (L-VDCC OE) in transgenic mice results in adaptive hypertrophy followed by a maladaptive phase associated with a decrease in sarcoplasmic reticulum adenosine triphosphatase (SERCA)2a expression at 8 to 10 months o... Full description

Journal Title: Journal of Cardiovascular Pharmacology and Therapeutics October 2005, Vol.10(4), pp.235-249
Main Author: Rubio, Marta
Other Authors: Bodi, Ilona , Fuller-Bicer, Geraldine A , Hahn, Harvey S , Periasamy, Muthu , Schwartz, Arnold
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 1074-2484 ; E-ISSN: 1940-4034 ; DOI: 10.1177/107424840501000404
Link: https://journals.sagepub.com/doi/full/10.1177/107424840501000404
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title: Sarcoplasmic Reticulum Adenosine Triphosphatase Overexpression in the L-type Ca2+ Channel Mouse Results in Cardiomyopathy and Ca2+-Induced Arrhythmogenesis
format: Article
creator:
  • Rubio, Marta
  • Bodi, Ilona
  • Fuller-Bicer, Geraldine A
  • Hahn, Harvey S
  • Periasamy, Muthu
  • Schwartz, Arnold
subjects:
  • L-Type Voltage-Dependent Calcium Channel
  • Sarcoplasmic Reticulum Adenosinetriphosphatase
  • Augmented Ca2+ Cycling
  • Medicine
  • Pharmacy, Therapeutics, & Pharmacology
ispartof: Journal of Cardiovascular Pharmacology and Therapeutics, October 2005, Vol.10(4), pp.235-249
description: Background: Overexpression of the L-type voltage-dependent calcium channel α1C-subunit (L-VDCC OE) in transgenic mice results in adaptive hypertrophy followed by a maladaptive phase associated with a decrease in sarcoplasmic reticulum adenosine triphosphatase (SERCA)2a expression at 8 to 10 months of age. Overexpressing SERCA to manipulate calcium (Ca2+) cycling and prevent pathologic phenotypes in some models of heart failure has been proven to be a promising genetic strategy. Objective: In this study we investigated whether genetic manipulation that increases Ca2+ uptake into the sarcoplasmic reticulum by overexpressing SERCA1a (skeletal muscle specific) into the L-VDCC OE background could restore or further deteriorate Ca2+ cycling, contractile dysfunction, and electrical remodeling in the heart failure phenotype. Results: We found that the survival rate of L-VDCC OE/SERCA1a OE double transgenic mice decreased by 50%. L-VDCC OE/SERCA1a OE mice displayed an accelerated phenotype of severe dilation of both ventricles associated with deteriorated left ventricular function. Voltage clamp experiments revealed enhanced increased inward Ca2+ current density and decreased the transient outward potassium current. Action potential duration in double transgenic ventricular myocytes was prolonged, and isoproterenol induced early afterdepolarization. These mice demonstrated a high incidence of spontaneous left ventricular arrhythmia. Expression of the proarrhythmic signaling protein Ca2+/calmodulin-dependent kinase II (CaMKII) was increased while connexin43 expression was decreased, defining an important putative mechanism in the electrophysiologic disturbances and mortality. Conclusions: Despite previous reports of improved cardiac function in heart failure models after SERCA intervention, our results advocate the need to elucidate the involvement of augmented Ca2+ cycling in arrhythmogenesis.
language: eng
source:
identifier: ISSN: 1074-2484 ; E-ISSN: 1940-4034 ; DOI: 10.1177/107424840501000404
fulltext: fulltext
issn:
  • 1074-2484
  • 10742484
  • 1940-4034
  • 19404034
url: Link


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titleSarcoplasmic Reticulum Adenosine Triphosphatase Overexpression in the L-type Ca2+ Channel Mouse Results in Cardiomyopathy and Ca2+-Induced Arrhythmogenesis
creatorRubio, Marta ; Bodi, Ilona ; Fuller-Bicer, Geraldine A ; Hahn, Harvey S ; Periasamy, Muthu ; Schwartz, Arnold
ispartofJournal of Cardiovascular Pharmacology and Therapeutics, October 2005, Vol.10(4), pp.235-249
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subjectL-Type Voltage-Dependent Calcium Channel ; Sarcoplasmic Reticulum Adenosinetriphosphatase ; Augmented Ca2+ Cycling ; Medicine ; Pharmacy, Therapeutics, & Pharmacology
descriptionBackground: Overexpression of the L-type voltage-dependent calcium channel α1C-subunit (L-VDCC OE) in transgenic mice results in adaptive hypertrophy followed by a maladaptive phase associated with a decrease in sarcoplasmic reticulum adenosine triphosphatase (SERCA)2a expression at 8 to 10 months of age. Overexpressing SERCA to manipulate calcium (Ca2+) cycling and prevent pathologic phenotypes in some models of heart failure has been proven to be a promising genetic strategy. Objective: In this study we investigated whether genetic manipulation that increases Ca2+ uptake into the sarcoplasmic reticulum by overexpressing SERCA1a (skeletal muscle specific) into the L-VDCC OE background could restore or further deteriorate Ca2+ cycling, contractile dysfunction, and electrical remodeling in the heart failure phenotype. Results: We found that the survival rate of L-VDCC OE/SERCA1a OE double transgenic mice decreased by 50%. L-VDCC OE/SERCA1a OE mice displayed an accelerated phenotype of severe dilation of both ventricles associated with deteriorated left ventricular function. Voltage clamp experiments revealed enhanced increased inward Ca2+ current density and decreased the transient outward potassium current. Action potential duration in double transgenic ventricular myocytes was prolonged, and isoproterenol induced early afterdepolarization. These mice demonstrated a high incidence of spontaneous left ventricular arrhythmia. Expression of the proarrhythmic signaling protein Ca2+/calmodulin-dependent kinase II (CaMKII) was increased while connexin43 expression was decreased, defining an important putative mechanism in the electrophysiologic disturbances and mortality. Conclusions: Despite previous reports of improved cardiac function in heart failure models after SERCA intervention, our results advocate the need to elucidate the involvement of augmented Ca2+ cycling in arrhythmogenesis.
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titleSarcoplasmic Reticulum Adenosine Triphosphatase Overexpression in the L-type Ca2+ Channel Mouse Results in Cardiomyopathy and Ca2+-Induced Arrhythmogenesis
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Background: Overexpression of the L-type voltage-dependent calcium channel α1C-subunit (L-VDCC OE) in transgenic mice results in adaptive hypertrophy followed by a maladaptive phase associated with a decrease in sarcoplasmic reticulum adenosine triphosphatase (SERCA)2a expression at 8 to 10 months of age. Overexpressing SERCA to manipulate calcium (Ca2+) cycling and prevent pathologic phenotypes in some models of heart failure has been proven to be a promising genetic strategy. Objective: In this study we investigated whether genetic manipulation that increases Ca2+ uptake into the sarcoplasmic reticulum by overexpressing SERCA1a (skeletal muscle specific) into the L-VDCC OE background could restore or further deteriorate Ca2+ cycling, contractile dysfunction, and electrical remodeling in the heart failure phenotype. Results: We found that the survival rate of L-VDCC OE/SERCA1a OE double transgenic mice decreased by 50%. L-VDCC OE/SERCA1a OE mice displayed an accelerated phenotype of severe dilation of both ventricles associated with deteriorated left ventricular function. Voltage clamp experiments revealed enhanced increased inward Ca2+ current density and decreased the transient outward potassium current. Action potential duration in double transgenic ventricular myocytes was prolonged, and isoproterenol induced early afterdepolarization. These mice demonstrated a high incidence of spontaneous left ventricular arrhythmia. Expression of the proarrhythmic signaling protein Ca2+/calmodulin-dependent kinase II (CaMKII) was increased while connexin43 expression was decreased, defining an important putative mechanism in the electrophysiologic disturbances and mortality. Conclusions: Despite previous reports of improved cardiac function in heart failure models after SERCA intervention, our results advocate the need to elucidate the involvement of augmented Ca2+ cycling in arrhythmogenesis.

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titleSarcoplasmic Reticulum Adenosine Triphosphatase Overexpression in the L-type Ca2+ Channel Mouse Results in Cardiomyopathy and Ca2+-Induced Arrhythmogenesis
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Background: Overexpression of the L-type voltage-dependent calcium channel α1C-subunit (L-VDCC OE) in transgenic mice results in adaptive hypertrophy followed by a maladaptive phase associated with a decrease in sarcoplasmic reticulum adenosine triphosphatase (SERCA)2a expression at 8 to 10 months of age. Overexpressing SERCA to manipulate calcium (Ca2+) cycling and prevent pathologic phenotypes in some models of heart failure has been proven to be a promising genetic strategy. Objective: In this study we investigated whether genetic manipulation that increases Ca2+ uptake into the sarcoplasmic reticulum by overexpressing SERCA1a (skeletal muscle specific) into the L-VDCC OE background could restore or further deteriorate Ca2+ cycling, contractile dysfunction, and electrical remodeling in the heart failure phenotype. Results: We found that the survival rate of L-VDCC OE/SERCA1a OE double transgenic mice decreased by 50%. L-VDCC OE/SERCA1a OE mice displayed an accelerated phenotype of severe dilation of both ventricles associated with deteriorated left ventricular function. Voltage clamp experiments revealed enhanced increased inward Ca2+ current density and decreased the transient outward potassium current. Action potential duration in double transgenic ventricular myocytes was prolonged, and isoproterenol induced early afterdepolarization. These mice demonstrated a high incidence of spontaneous left ventricular arrhythmia. Expression of the proarrhythmic signaling protein Ca2+/calmodulin-dependent kinase II (CaMKII) was increased while connexin43 expression was decreased, defining an important putative mechanism in the electrophysiologic disturbances and mortality. Conclusions: Despite previous reports of improved cardiac function in heart failure models after SERCA intervention, our results advocate the need to elucidate the involvement of augmented Ca2+ cycling in arrhythmogenesis.

copThousand Oaks, CA
pubSage Publications
doi10.1177/107424840501000404
date2005-10