Ablation of a Single N-Glycosylation Site in Human FSTL 1 Induces Cardiomyocyte Proliferation and Cardiac Regeneration.
Ablation of a Single N-Glycosylation Site in Human FSTL 1 Induces Cardiomyocyte Proliferation and Cardiac Regeneration.
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DOI：
10.1016/j.omtn.2018.08.021
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发表时间：
2018-12-07
期刊：
影响因子：
--
通讯作者：
Zangi L
中科院分区：
文献类型：
--
作者：
Magadum A;Singh N;Kurian AA;Sharkar MTK;Chepurko E;Zangi L
成年哺乳动物心脏的再生能力非常有限，这主要是由于缺乏心肌细胞（CM）增殖。最近有报道称，心肌梗塞 (MI) 后，心外膜而非心肌的卵泡抑素样 1 (Fstl1) 可激活 CM 增殖和心脏再生。此外，发现细菌合成的人类 FSTL 1 (hFSTL1) 可诱导 CM 增殖，而哺乳动物中合成的 hFSTL1 则不会，这表明 hFSTL1 蛋白的翻译后修饰（例如糖基化）会影响其再生活性。我们使用修饰的 mRNA (modRNA) 技术来研究特定 hFSTL1 N-糖基化位点在 hFSTL1 诱导 CM 增殖和心脏再生中的可能作用。我们发现，单个位点 (N180Q) 的突变对于分别增加大鼠新生儿和小鼠成年 CM 的体外增殖和 MI 后体内增殖是充分且必要的。编码 N180Q 突变体的 modRNA 构建体的单次给药可显着增强心肌梗死后 28 天的心脏功能、缩小疤痕大小并增加毛细血管密度。总体而言，我们的数据表明，将 N180Q hFSTL1 modRNA 递送至心肌可以模拟心外膜 hFSTL1 的有益作用，在小鼠 MI 模型中触发显着的 CM 增殖和心脏再生。
Adult mammalian hearts have a very limited regeneration capacity, due largely to a lack of cardiomyocyte (CM) proliferation. It was recently reported that epicardial, but not myocardial, follistatin-like 1 (Fstl1) activates CM proliferation and cardiac regeneration after myocardial infarction (MI). Furthermore, bacterially synthesized human FSTL 1 (hFSTL1) was found to induce CM proliferation, whereas hFSTL1 synthesized in mammals did not, suggesting that post-translational modifications (e.g., glycosylation) of the hFSTL1 protein affect its regenerative activity. We used modified mRNA (modRNA) technology to investigate the possible role of specific hFSTL1 N-glycosylation sites in the induction, by hFSTL1, of CM proliferation and cardiac regeneration. We found that the mutation of a single site (N180Q) was sufficient and necessary to increase the proliferation of rat neonatal and mouse adult CMs in vitro and after MI in vivo, respectively. A single administration of the modRNA construct encoding the N180Q mutant significantly increased cardiac function, decreased scar size, and increased capillary density 28 days post-MI. Overall, our data suggest that the delivery of N180Q hFSTL1 modRNA to the myocardium can mimic the beneficial effect of epicardial hFSTL1, triggering marked CM proliferation and cardiac regeneration in a mouse MI model.
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DOI：
10.1126/science.1199010
发表时间：
2011-04-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Heallen T;Zhang M;Wang J;Bonilla-Claudio M;Klysik E;Johnson RL;Martin JF
通讯作者：
Martin JF
影响因子：
4.6
作者：
Heallen, Todd;Morikawa, Yuka;Martin, James F.
通讯作者：
Martin, James F.
影响因子：
64.5
作者：
Bersell, Kevin;Arab, Shima;Kuehn, Bernhard
通讯作者：
Kuehn, Bernhard
影响因子：
21.3
作者：
D'Uva, Gabriele;Aharonov, Alla;Tzahor, Eldad
通讯作者：
Tzahor, Eldad
DOI：
10.1161/hhf.0b013e318291329a
发表时间：
2013-05
期刊：
Circulation. Heart failure
影响因子：
--
作者：
Heidenreich PA;Albert NM;Allen LA;Bluemke DA;Butler J;Fonarow GC;Ikonomidis JS;Khavjou O;Konstam MA;Maddox TM;Nichol G;Pham M;Piña IL;Trogdon JG;American Heart Association Advocacy Coordinating Committee;Council on Arteriosclerosis, Thrombosis and Vascular Biology;Council on Cardiovascular Radiology and Intervention;Council on Clinical Cardiology;Council on Epidemiology and Prevention;Stroke Council
通讯作者：
Stroke Council