Recovery of Left ventricular function following in vivo reexpression of cardiac myosin binding protein C
Recovery of Left ventricular function following in vivo reexpression of cardiac myosin binding protein C
复制标题
DOI：
10.1085/jgp.201812238
复制
发表时间：
2019-01-01
影响因子：
3.8
通讯作者：
Moss, Richard L.
中科院分区：
文献类型：
--
作者：
Giles, Jasmine;Patel, Jitandrakumar R.;Moss, Richard L.
心肌肌球蛋白结合蛋白C（cMyBP-C）的缺失导致组成性和条件性cMyBP-C敲除（MYBPC 3 null）小鼠的左心室扩张、心脏肥大和心室功能受损。目前尚不清楚MYBPC 3敲除小鼠中表达的结构和功能表型是否可逆，这是一个重要的问题，因为cMyBP-C表达减少是人类肥厚型心肌病的重要原因。为了研究这个问题，我们使用Tet-Off诱导系统产生了心脏特异性转基因小鼠模型，以允许在MYBPC 3无效背景上控制WT cMyBP-C的表达。通过将四环素反式激活因子小鼠与携带WT cMyBP-C转基因的应答小鼠杂交，产生表达WT cMyBP-C的功能性Tet-Off小鼠（FT-WT）。在饮食给予强力霉素之前，cMyBP-C在FT-WT心肌中以正常水平表达，其表现出与WT小鼠相似的稳态力水平和体内左心室功能。饮食中引入强力霉素4周导致cMyBP-C表达的部分敲低和收缩和舒张功能的相应损害，接近在MYBPC 3缺失小鼠中观察到的水平。随后从饮食中撤出强力霉素导致cMyBP-C的重新表达达到与WT小鼠中观察到的水平相当的水平，沿着体内心室功能的几乎完全恢复。这些结果表明，与MYBPC 3缺失小鼠相关的心脏表型是可逆的。我们的工作也验证了使用Tet-Off诱导系统作为一种手段来研究肥厚型心肌病的机制。
The loss of cardiac myosin binding protein C (cMyBP-C) results in left ventricular dilation, cardiac hypertrophy, and impaired ventricular function in both constitutive and conditional cMyBP-C knockout (MYBPC3 null) mice. It remains unclear whether the structural and functional phenotypes expressed in the MYBPC3 null mouse are reversible, which is an important question, since reduced expression of cMyBP-C is an important cause of hypertrophic cardiomyopathy in humans. To investigate this question, we generated a cardiac-specific transgenic mouse model using a Tet-Off inducible system to permit the controlled expression of WT cMyBP-C on the MYBPC3 null background. Functional Tet-Off mice expressing WT cMyBP-C (FT-WT) were generated by crossing tetracycline transactivator mice with responder mice carrying the WT cMyBP-C transgene. Prior to dietary doxycycline administration, cMyBP-C was expressed at normal levels in FT-WT myocardium, which exhibited similar levels of steady-state force and in vivo left ventricular function as WT mice. Introduction of dietary doxycycline for four weeks resulted in a partial knockdown of cMyBP-C expression and commensurate impairment of systolic and diastolic function to levels approaching those observed in MYBPC3 null mice. Subsequent withdrawal of doxycycline from the diet resulted in the reexpression of cMyBP-C to levels comparable to those observed in WT mice, along with nearcomplete recovery of in vivo ventricular function. These results show that the cardiac phenotypes associated with MYBPC3 null mice are reversible. Our work also validates the use of the Tet-Off inducible system as a means to study the mechanisms underlying hypertrophic cardiomyopathy.