BACKGROUND: Overexpression of the L-type voltage-dependent calcium channel alpha(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 (Ca(2+)) 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 Ca(2+) uptake into the sarcoplasmic reticulum by overexpressing SERCA1a (skeletal muscle specific) into the L-VDCC OE background could restore or further deteriorate Ca(2+) 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 Ca(2+) current density and decreased the transient outward potassium current. Action potential duration in double transgenic ventricular myocytes was prolonged, and isoproterenol induced early after depolarization. These mice demonstrated a high incidence of spontaneous left ventricular arrhythmia. Expression of the proarrhythmic signaling protein Ca(2+)/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 Ca(2+) cycling in arrhythmogenesis.
BACKGROUND: Overexpression of the L-type voltage-dependent calcium channel alpha(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 (Ca(2+)) 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 Ca(2+) uptake into the sarcoplasmic reticulum by overexpressing SERCA1a (skeletal muscle specific) into the L-VDCC OE background could restore or further deteriorate Ca(2+) 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 Ca(2+) current density and decreased the transient outward potassium current. Action potential duration in double transgenic ventricular myocytes was prolonged, and isoproterenol induced early after depolarization. These mice demonstrated a high incidence of spontaneous left ventricular arrhythmia. Expression of the proarrhythmic signaling protein Ca(2+)/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 Ca(2+) cycling in arrhythmogenesis.
Authors: J Michael O'Donnell; Aaron Fields; Xianyao Xu; Shamim A K Chowdhury; David L Geenen; Jian Bi Journal: Am J Physiol Heart Circ Physiol Date: 2008-10-24 Impact factor: 4.733