Knollmann B C, Blatt S A, Horton K, de Freitas F, Miller T, Bell M, Housmans P R, Weissman N J, Morad M, Potter J D
Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Georgetown University Medical Center, Washington, D. C. 20007, USA.
J Biol Chem. 2001 Mar 30;276(13):10039-48. doi: 10.1074/jbc.M006745200. Epub 2000 Dec 11.
The cardiac troponin T (TnT) I79N mutation has been linked to familial hypertrophic cardiomyopathy and a high incidence of sudden death, despite causing little or no cardiac hypertrophy. In skinned fibers, I79N increased myofilamental calcium sensitivity (Miller, T., Szczesna, D., Housmans, P. R., Zhao, J., deFreitas, F., Gomes, A. V., Culbreath, L., McCue, J., Wang, Y., Xu, Y., Kerrick, W. G., and Potter, J. D. (2001) J. Biol. Chem. 276, 3743-3755). To further study the functional consequences of this mutation, we compared the cardiac performance of transgenic mice expressing either human TnT-I79N or human wild-type TnT. In isolated hearts, cardiac function was different depending on the Ca(2+) concentration of the perfusate; systolic function was significantly increased in Tg-I79N hearts at 0.5 and 1 mmol/liter. At higher Ca(2+) concentrations, systolic function was not different, but diastolic dysfunction became manifest as increased end-diastolic pressure and time to 90% relaxation. In vivo measurements by echocardiography and Doppler confirmed that base-line systolic function was significantly higher in Tg-I79N mice without evidence for diastolic dysfunction. Inotropic stimulation with isoproterenol resulted only in a modest contractile response but caused significant mortality in Tg-I79N mice. Doppler studies ruled out aortic outflow obstruction and were consistent with increased chamber stiffness. We conclude that in vivo, the increased myofilament Ca(2+) sensitivity due to the I79N mutation enhances base-line contractility but leads to cardiac dysfunction during inotropic stimulation.
心肌肌钙蛋白T（TnT）的I79N突变与家族性肥厚型心肌病及猝死的高发生率有关，尽管该突变几乎不会引起或根本不会引起心肌肥厚。在去表皮肌纤维中，I79N增加了肌丝对钙的敏感性（米勒，T.，斯切斯纳，D.，豪斯曼斯，P.R.，赵，J.，德弗雷塔斯，F.，戈麦斯，A.V.，卡尔布雷思，L.，麦库，J.，王，Y.，徐，Y.，克里克，W.G.，以及波特，J.D.（2001年）《生物化学杂志》276卷，3743 - 3755页）。为了进一步研究该突变的功能后果，我们比较了表达人TnT - I79N或人野生型TnT的转基因小鼠的心脏功能。在离体心脏中，心脏功能因灌注液中Ca(2+)浓度的不同而有所差异；在0.5和1毫摩尔/升时，Tg - I79N心脏的收缩功能显著增强。在较高的Ca(2+)浓度下，收缩功能没有差异，但舒张功能障碍表现为舒张末期压力升高和90%舒张时间延长。通过超声心动图和多普勒进行的体内测量证实，Tg - I79N小鼠的基线收缩功能显著更高，且无舒张功能障碍的证据。用异丙肾上腺素进行变力刺激仅导致适度的收缩反应，但在Tg - I79N小鼠中引起了显著的死亡率。多普勒研究排除了主动脉流出道梗阻，并与心室僵硬度增加一致。我们得出结论，在体内，I79N突变导致的肌丝对Ca(2+)敏感性增加增强了基线收缩性，但在变力刺激期间导致心脏功能障碍。
