Investigation of a transgenic mouse model of familial dilated cardiomyopathy

详细信息    查看全文

• 作者：Weihua Song ; Emma Dyer ; Daniel Stuckey ; Man-Ching Leung ; Massimiliano Memo ; Catherine Mansfield ; Michael Ferenczi ; Ke Liu ; Charles Redwood ; Kristen Nowak ; Sian Harding ; Kieran Clarke ; Dominic Wells ; S
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2010
• 出版时间：September 2010
• 年：2010
• 卷：49
• 期：3
• 页码：380-389
• 全文大小：1624 K

文摘

We have investigated a transgenic mouse model of inherited dilated cardiomyopathy that stably expresses the ACTC E361G mutation at around 50 % of total actin in the heart. F-actin isolated from ACTC E361G mouse hearts was incorporated into thin filaments with native human tropomyosin and troponin and compared with NTG mouse actin by in vitro motility assay. There was no significant difference in sliding speed, fraction of filaments motile or Ca²⁺-sensitivity (ratio EC₅₀ E361G/NTG = 0.95 ± 0.08). The Ca²⁺-sensitivity of force in skinned trabeculae from ACTC E361G mice was slightly higher than NTG (EC₅₀ E361G/NTG = 0.78 ± 0.04). The molecular phenotype was revealed when troponin was dephosphorylated; Ca²⁺-sensitivity of E361G-containing thin filaments was now lower than NTG (EC₅₀ E361G_dPTn/NTG_dPTn = 2.15 ± 0.09). We demonstrated that this was due to uncoupling of Ca²⁺-sensitivity from troponin I phosphorylation by comparing Ca²⁺-sensitivity of phosphorylated and dephosphorylated thin filaments. For NTG actin-containing thin filaments EC₅₀ native/dPTn = 3.0 ± 0.3 but for E361G-containing thin filaments EC₅₀ native/dPTn = 1.04 ± 0.07.We studied contractility in isolated myocytes and found no significant differences under basal conditions. We measured cardiac performance by cine-MRI, echocardiography and with a conductance catheter over a period of 4 to 18 months and found minimal systematic differences between NTG and ACTC E361G mice under basal conditions. However, the increase in septal thickening, ejection fraction, heart rate and cardiac output following dobutamine treatment was significantly less in ACTC E361G mice compared with NTG. We propose that the ACTC E361G mutation uncouples myofilament Ca²⁺-sensitivity from Troponin I phosphorylation and blunts the response to adrenergic stimulation, leading to a reduced cardiac reserve with consequent contractile dysfunction under stress, leading to dilated cardiomyopathy.