作者：Xupei. Huang Larry.F.Lemanski Jeffery. W.Walker
单位：Xupei. Huang(Department of Medical Physiology,Texas A&M University System HSC, College Station, TX 77843;)；Larry.F.Lemanski(Department of Medical Physiology,Texas A&M University System HSC, College Station, TX 77843)
关键词：
中国病理生理杂志001030 Jeffery. W.Walker
( Department of Physiology, University of Wisconsin, Madison, WI 53706)
Troponin I(TnI) is a subunit of the thin filament-associated troponin-tropomyosin complex involved in calcium regulation of skeletal and cardiac muscle contraction. We deleted the cardiac isoform of troponin I(cTnI) by using gene targeting in murine embryonic stem cells to determine the developmental and physiological effects of the absence of this regulatory protein. Mice lacking cTnI were born healthy, with normal heart and body weight, because a fetal TnI isoform (identical to slow skeletal TnI, ssTnI) compensated for the absence of cTnI. Compensation was only temporary, however, as 15 days after birth ssTnI expression began a steady decline, giving rise to a TnI deficiency. Mice died of acute heart failure on day 18, demonstrating that some form of TnI is required for normal cardiac function and survival. Ventricular myocytes isolated from these TnI-depleted hearts displayed shortened sarcomeres and elevated resting tension measured under relaxing conditions. The results show that cTnI depletion alters specific mechanical properties of myocardium and can lead to a lethal from of acute heart failure. In addition, we have investigated the mechanism underlying the down-regulation of fetal TnI gene expression during heart development by using the cTnI null mice with hypo-or hyper-thyroid status. Overall, the results indicate that inactivation of the ssTnI gene occurs even in the absence of cTnI mRNA and protein indicating that these are not critical signals for ssTnI down-regulation in the heart. In contrast, thyroid hormone influences the time course of ssTnI expression and may therefore play a role in ssTnI inactivation during heart development.
* Supported by a Grant-in-Aid from National American Heart Association
(Xupei. Huang Larry.F.Lemanski Jeffery. W.Walker)
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