Pressure Overload in Mice With Haploinsufficiency of Striated Preferentially Expressed Gene Leads to Decompensated Heart Failure.
Pressure Overload in Mice With Haploinsufficiency of Striated Preferentially Expressed Gene Leads to Decompensated Heart Failure.
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DOI：
10.3389/fphys.2018.00863
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发表时间：
2018
影响因子：
4
通讯作者：
Perrella MA
中科院分区：
文献类型：
--
作者：
Shu C;Huang H;Xu Y;Rota M;Sorrentino A;Peng Y;Padera RF Jr;Huntoon V;Agrawal PB;Liu X;Perrella MA
Striated preferentially expressed gene（Speg）是肌球蛋白轻链激酶家族的成员。组成型Speg缺陷（Speg−/−）小鼠会发生扩张型心肌病，大多数小鼠在子宫内或出生后不久死亡。在本研究中，我们评估了Speg在成年小鼠中的重要性。存活至成年的Speg−/−小鼠或成年横纹肌特异性Speg基因敲除小鼠（Speg-KO）表现出心功能不全和左心室（LV）内径和心脏与体重比增加的证据。为了确定Speg的杂合性是否干扰心脏对病理生理应激的反应，Speg+/−小鼠暴露于由横向主动脉缩窄（TAC）诱导的压力超负荷。在基线时，Speg+/+和Speg+/−心脏显示心脏功能无差异。然而，TAC后4周，Speg+/−小鼠的LV功能显著降低。与TAC后的Speg+/+小鼠相比，该缺陷与LV内径增加和心脏重量与体重比增加相关。与Speg+/+小鼠相比，Speg+/−小鼠对压力超负荷的反应还包括心肌纤维化沉积增加、横小管破坏和细胞收缩力减弱。总之，这些数据表明，Speg是正常心脏功能所必需的，并参与心脏对TAC的复杂适应。当暴露于压力超负荷时，Speg的单倍不足导致失代偿性心力衰竭。
Striated preferentially expressed gene (Speg) is a member of the myosin light chain kinase family of proteins. Constitutive Speg deficient (Speg−/−) mice develop a dilated cardiomyopathy, and the majority of these mice die in utero or shortly after birth. In the present study we assessed the importance of Speg in adult mice. Speg−/− mice that survived to adulthood, or adult striated muscle-specific Speg knockout mice (Speg-KO), demonstrated cardiac dysfunction and evidence of increased left ventricular (LV) internal diameter and heart to body weight ratio. To determine whether heterozygosity of Speg interferes with the response of the heart to pathophysiologic stress, Speg+/− mice were exposed to pressure overload induced by transverse aortic constriction (TAC). At baseline, Speg+/+ and Speg+/− hearts showed no difference in cardiac function. However, 4 weeks after TAC, Speg+/− mice had a marked reduction in LV function. This defect was associated with an increase in LV internal diameter and enhanced heart weight to body weight ratio, compared with Speg+/+ mice after TAC. The response of Speg+/− mice to pressure overload also included increased fibrotic deposition in the myocardium, disruption of transverse tubules, and attenuation in cell contractility, compared with Speg+/+ mice. Taken together, these data demonstrate that Speg is necessary for normal cardiac function and is involved in the complex adaptation of the heart in response to TAC. Haploinsufficiency of Speg results in decompensated heart failure when exposed to pressure overload.
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