Key result
Overexpressing SERCA1a in L-VDCC overexpressing mice decreased survival by 50% and accelerated severe biventricular dilation, contractile dysfunction, and arrhythmogenesis.
Why the study?
Does SERCA1a overexpression improve or deteriorate contractile dysfunction and electrical remodeling in L-VDCC OE transgenic mice?
Does SERCA1a overexpression improve or deteriorate contractile dysfunction and electrical remodeling in L-VDCC OE transgenic mice?
Overexpressing SERCA1a in a heart failure mouse model driven by L-type calcium channel overexpression worsens survival and exacerbates cardiomyopathy and arrhythmogenesis, challenging the universal benefit of SERCA interventions.
SERCA1a overexpression may worsen L-VDCC cardiomyopathy; challenges universal SERCA benefit and leaves open subtype-specific effects.
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.
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Rubio et al. (2005) studied Cardiomyopathy and heart failure. SERCA1a overexpression vs. L-VDCC OE background was evaluated on Survival rate and cardiac phenotype. Overexpressing SERCA1a in L-VDCC overexpressing mice decreased survival by 50% and accelerated severe biventricular dilation, contractile dysfunction, and arrhythmogenesis.
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