LncRNA LncHrt preserves cardiac metabolic homeostasis and heart function by modulating the LKB1-AMPK signaling pathway.
LncRNA LncHrt preserves cardiac metabolic homeostasis and heart function by modulating the LKB1-AMPK signaling pathway.
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DOI：
10.1007/s00395-021-00887-3
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发表时间：
2021-08-11
影响因子：
9.5
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Liu N;Kataoka M;Wang Y;Pu L;Dong X;Fu X;Zhang F;Gao F;Liang T;Pei J;Xiao C;Qiu Q;Hong T;Chen Q;Zhao J;Zhu L;He J;Hu X;Nie Y;Zhu W;Yu H;Cowan DB;Hu X;Wang J;Wang DZ;Chen J
代谢调节是预防缺血性心脏不良重构的一种有前途的治疗方法。由于对长链非编码RNA（lncRNA）参与调节心脏代谢知之甚少，我们在心肌梗死（MI）小鼠模型中使用了无偏转录组分析。我们发现了一种新的心肌细胞富集的lncRNA，称为LncHrt，它调节代谢和导致心力衰竭的病理生理过程。基于AAV的LncHrt过表达保护心脏免受MI，如通过改善的收缩功能、保持的代谢稳态和减弱的适应不良重构反应所证明的。RNA下拉质谱和RNA免疫沉淀（RIP）确定SIRT 2作为一个LncHrt相互作用蛋白参与心脏代谢调节。从机制上讲，我们建立了LncHrt与SIRT 2相互作用，通过干扰CDK 5和SIRT 2相互作用来保持SIRT 2脱乙酰酶活性。这增加下游LKB 1-AMPK激酶信号传导，从而改善功能和代谢缺陷。重要的是，我们发现扩张型心肌病患者中小鼠LncHrt的人类同源物的表达降低。总之，这些研究将LncHrt确定为心脏代谢调节剂，其通过调节下游代谢信号传导途径在保护心脏功能方面发挥重要作用。因此，LncHrt是一个潜在的新的基于RNA的缺血性心脏病的治疗靶点。在线版本包含补充材料，可通过10.1007/s 00395 -021-00887-3获得。
Metabolic modulation is a promising therapeutic approach to prevent adverse remodeling of the ischemic heart. Because little is known about the involvement of long non-coding RNAs (lncRNAs) in regulating cardiac metabolism, we used unbiased transcriptome profiling in a mouse model of myocardial infarction (MI). We identified a novel cardiomyocyte-enriched lncRNA, called LncHrt, which regulates metabolism and the pathophysiological processes that lead to heart failure. AAV-based LncHrt overexpression protects the heart from MI as demonstrated by improved contractile function, preserved metabolic homeostasis, and attenuated maladaptive remodeling responses. RNA-pull down followed by mass spectrometry and RNA immunoprecipitation (RIP) identified SIRT2 as a LncHrt-interacting protein involved in cardiac metabolic regulation. Mechanistically, we established that LncHrt interacts with SIRT2 to preserve SIRT2 deacetylase activity by interfering with the CDK5 and SIRT2 interaction. This increases downstream LKB1-AMPK kinase signaling, which ameliorates functional and metabolic deficits. Importantly, we found the expression of the human homolog of mouse LncHrt was decreased in patients with dilated cardiomyopathy. Together, these studies identify LncHrt as a cardiac metabolic regulator that plays an essential role in preserving heart function by regulating downstream metabolic signaling pathways. Consequently, LncHrt is a potentially novel RNA-based therapeutic target for ischemic heart disease. The online version contains supplementary material available at 10.1007/s00395-021-00887-3.
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影响因子：
7.4
作者：
Ku, Hyeong Jun;Ahn, Youngkeun;Park, Jeen-Woo
通讯作者：
Park, Jeen-Woo
影响因子：
6.6
作者：
Bras, Lisandra E. de Castro;Cates, Courtney A.;Lindsey, Merry L.
通讯作者：
Lindsey, Merry L.
DOI：
10.1152/ajpheart.00945.2015
发表时间：
2016-11-01
影响因子：
4.8
作者：
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通讯作者：
Driesen, Ronald B.
影响因子：
3.6
作者：
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通讯作者：
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影响因子：
29
作者：
Cantó C;Jiang LQ;Deshmukh AS;Mataki C;Coste A;Lagouge M;Zierath JR;Auwerx J
通讯作者：
Auwerx J