Article ID Journal Published Year Pages File Type
10954247 Journal of Molecular and Cellular Cardiology 2008 10 Pages PDF
Abstract
Mechanical and biochemical alterations were investigated in permeabilized cardiomyocytes along with the progression of dilated cardiomyopathy (DCM) in a transgenic mouse line overexpressing the activated Gαq protein (Tgαq*44). The isometric force, its Ca2+ sensitivity (pCa50) and the turnover rate of the actin-myosin cycle (ktr) were determined at sarcomere lengths (SLs) of 1.9 μm and 2.3 μm before (at 4 and 10 months of age) and after hemodynamic decompensation (at 14 and 18 months of age) in Tgαq*44 cardiomyocytes and in age-matched control cardiomyocytes. The SL-dependence of pCa50 was not different in Tgαq*44 and control hearts. In contrast, a significant increase in pCa50 was observed in the Tgαq*44 cardiomyocytes (ΔpCa50: 0.10-0.15 vs. the controls) after 10 months of age that could be diminished by exposures to the catalytic subunit of protein kinase A (PKA). Accordingly, a decline in endogenous PKA activity and decreased troponin I phosphorylation were detected after 10 months in the Tgαq*44 hearts. Finally, the maximal Ca2+-activated force (Fo) and ktr were lower and the passive force (Fpassive) was higher at 18 months in the Tgαq*44 cardiomyocytes compared to the control. These mechanical alterations were paralleled by a robust increase in β-myosin heavy chain expression in the Tgαq*44 hearts. In conclusion, our data suggested that an initial decrease of PKA signaling and subsequent changes in myofilament protein expression may contribute to the development of dilated cardiomyopathy in Tgαq*44 hearts.
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