| Sign In to gain access to subscriptions and/or personal tools. |
Sarcoplasmic Reticulum Adenosine Triphosphatase Overexpression in the L-type Ca2+ Channel Mouse Results in Cardiomyopathy and Ca2+-Induced ArrhythmogenesisInstitute of Molecular Pharmacology and Biophysics, University of Cincinnati Medical Center, Cincinnati
Institute of Molecular Pharmacology and Biophysics, University of Cincinnati Medical Center, Cincinnati
Institute of Molecular Pharmacology and Biophysics, University of Cincinnati Medical Center, Cincinnati
Department of Internal Medicine, Division of Cardiology, University of Cincinnati Medical Center, Cincinnati
Department of Physiology and Cell Biology, College of Medicine and Public Health, The Ohio State University, Columbus, OH
Institute of Molecular Pharmacology and Biophysics, University of Cincinnati Medical Center, Cincinnati
Background: Overexpression of the L-type voltage-dependent calcium channel 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.
Key Words: L-type voltage-dependent calcium channel • sarcoplasmic reticulum adenosinetriphosphatase • augmented Ca2+ cycling
Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 10, No. 4,
235-249 (2005) This article has been cited by other articles:
|
|||||||||||||||||||||||||||
 |
|
|
 |
Sign In to gain access to subscriptions and/or personal tools.
1C-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. 
