【摘 要】
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The Ca2+ sensitivity of cardiac muscle force development can be adversely altered during disease.Since troponin C (TnC) is the Ca2+ sensor for muscle contra
【机 构】
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DepartmentofPhysiologyandCellBiologyTheOhioStateUniversityUSA
【出 处】
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BITs 1rd Annual World Cancer Congress of Cardiology-2009(200
论文部分内容阅读
The Ca2+ sensitivity of cardiac muscle force development can be adversely altered during disease.Since troponin C (TnC) is the Ca2+ sensor for muscle contraction, TnCs Ca2+ binding properties may be altered by the disease related protein modifications.Consistent with the patho-physiology, the inherited restrictive cardiomyopathy (RCM) mutation TnI R192H and ischemia induced truncation of TnI (residues 1-192) increased TnCs Ca2+ binding sensitivity ~3 fold and ~8 fold respectively, while the dilated cardiomyopathy (DCM) mutation TnT delK210 decreased TnCs Ca2+ binding sensitivity ~3 fold.Since abnormal Ca2+ binding might be the potential cause for the disease symptoms,correcting the disease related abnormal Ca2+ binding might improve cardiac function.To achieve this goal, we have engineered TnC constructs with a wide range of Ca2+ binding sensitivities.The Ca2+ desensitizing TnC constructs were combined with the RCM TnI and truncated TnI to attenuate the disease related increased Ca2+ sensitivities; while a Ca2+ sensitizing TnC construct was combined with the DCM TnT to attenuate the disease related decreased Ca2+ sensitivity.Functionally, the engineered TnC constructs were also able to attenuate the disease related Ca2+-dependnet changes in myosin ATPase activity biochemically and force development physiologically.Thus, we were able to fine tune the Ca2+ sensitivity of TnC, allowing us to attenuate the disease induced abnormal Ca2+ binding.This study can potentially lead to a novel therapeutic strategy for treating cardiac muscle diseases.
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