A novel human S10F-Hsp20 mutation induces lethal peripartum cardiomyopathy.
A novel human S10F-Hsp20 mutation induces lethal peripartum cardiomyopathy.
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DOI：
10.1111/jcmm.13665
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发表时间：
2018-08
影响因子：
5.3
通讯作者：
Kranias EG
中科院分区：
文献类型：
--
作者：
Liu GS;Gardner G;Adly G;Jiang M;Cai WF;Lam CK;Alogaili F;Robbins N;Rubinstein J;Kranias EG
热休克蛋白20（Hsp 20）已被证明是心脏应激时心肌细胞存活的关键调节因子。在这项研究中，我们调查了一个新的人类热休克蛋白20突变（S10 F）在围产期心肌病的功能意义。先前的研究结果表明，这种突变体的心脏特异性过表达与雄性小鼠的自噬减少、左心室功能障碍和早期死亡有关。然而，这项研究表明，女性具有正常的功能，自噬没有改变，但在1 - 4次妊娠后一周内死亡。进一步检查突变体女性发现左心室腔扩张和肥厚性重塑。超声心动图显示左心室收缩末期容积和左心室舒张末期容积增加，而射血分数和缩短分数在妊娠后降低。随后的研究表明，在第三次分娩后，突变女性心脏中的心肌细胞凋亡增加，与Bcl-2/Bax和Akt磷酸化水平的降低相关。这些结果表明，人S10 F突变体与细胞存活信号传导失调、加速心力衰竭和产后早期死亡有关。
Heat shock protein 20 (Hsp20) has been shown to be a critical regulator of cardiomyocyte survival upon cardiac stress. In this study, we investigated the functional significance of a novel human Hsp20 mutation (S10F) in peripartum cardiomyopathy. Previous findings showed that cardiac‐specific overexpression of this mutant were associated with reduced autophagy, left ventricular dysfunction and early death in male mice. However, this study indicates that females have normal function with no alterations in autophagy but died within a week after 1‐4 pregnancies. Further examination of mutant females revealed left ventricular chamber dilation and hypertrophic remodelling. Echocardiography demonstrated increases in left ventricular end‐systolic volume and left ventricular end‐diastolic volume, while ejection fraction and fractional shortening were depressed following pregnancy. Subsequent studies revealed that cardiomyocyte apoptosis was elevated in mutant female hearts after the third delivery, associated with decreases in the levels of Bcl‐2/Bax and Akt phosphorylation. These results indicate that the human S10F mutant is associated with dysregulation of cell survival signalling, accelerated heart failure and early death post‐partum.
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