MiR-150 blunts cardiac dysfunction in mice with cardiomyocyte loss of β(1)-adrenergic receptor/β-arrestin signaling and controls a unique transcriptome.
MiR-150 blunts cardiac dysfunction in mice with cardiomyocyte loss of β(1)-adrenergic receptor/β-arrestin signaling and controls a unique transcriptome.
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DOI：
10.1038/s41420-022-01295-9
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发表时间：
2022-12-30
影响因子：
7
通讯作者：
Kim, Il-man
中科院分区：
文献类型：
--
作者：
Moukette, Bruno;Kawaguchi, Satoshi;Sepulveda, Marisa N.;Hayasaka, Taiki;Aonuma, Tatsuya;Liangpunsakul, Suthat;Yang, Lei;Dharmakumar, Rohan;Conway, Simon J.;Kim, Il-man
β1肾上腺素能受体(β1AR)主要存在于心脏(主要是心肌细胞)，β-arrestin介导的β1AR信号通过心肌存活而产生心脏保护作用。我们发现β-arrestin介导的β1AR信号上调了microRNA-150(miR-150)，而CM miR-150抑制了心肌梗死后的不良适应性重构。在这里，我们研究了MIR-150是否能挽救CM特异性阻断β-arrestin介导的β1AR信号转导的小鼠的心功能障碍。利用CM特异的转基因(TG)小鼠表达突变的β1AR(G蛋白偶联受体激酶-β1AR在β-arrestin介导的β1AR信号中表现出损伤)，我们首次建立了一个新的高表达miR-150的双转基因小鼠系。我们证明，miR-150足以改善慢性儿茶酚胺刺激后CM特异性Grk-β1AR TG小鼠的心功能障碍。我们的全基因组环状RNA、长非编码RNA(LncRNA)和信使核糖核酸图谱分析揭示了心脏ncRNA和基因的子集，这些都是迄今为止尚未认识的β1AR/β-arrestin信号或miR-150有益作用的机制。我们进一步证明，lncRNA Gm41664和GDAP1L1是miR-150的直接新的上下游调控因子。最后，miR-150的CM保护作用归因于抑制促凋亡的GDAP1L1，并被促凋亡的Gm41664缓解。我们的发现支持这一观点，即miR-150通过调节CMS中独特的ncRNA和基因信号，在β1AR/β-arrestin介导的心肌保护中发挥重要作用。
The β1-adrenergic receptor (β1AR) is found primarily in hearts (mainly in cardiomyocytes [CMs]) and β-arrestin-mediated β1AR signaling elicits cardioprotection through CM survival. We showed that microRNA-150 (miR-150) is upregulated by β-arrestin-mediated β1AR signaling and that CM miR-150 inhibits maladaptive remodeling post-myocardial infarction. Here, we investigate whether miR-150 rescues cardiac dysfunction in mice bearing CM-specific abrogation of β-arrestin-mediated β1AR signaling. Using CM-specific transgenic (TG) mice expressing a mutant β1AR (G protein-coupled receptor kinase [GRK]–β1AR that exhibits impairment in β-arrestin-mediated β1AR signaling), we first generate a novel double TG mouse line overexpressing miR-150. We demonstrate that miR-150 is sufficient to improve cardiac dysfunction in CM-specific GRK–β1AR TG mice following chronic catecholamine stimulation. Our genome-wide circular RNA, long noncoding RNA (lncRNA), and mRNA profiling analyses unveil a subset of cardiac ncRNAs and genes as heretofore unrecognized mechanisms for beneficial actions of β1AR/β-arrestin signaling or miR-150. We further show that lncRNA Gm41664 and GDAP1L1 are direct novel upstream and downstream regulators of miR-150. Lastly, CM protective actions of miR-150 are attributed to repressing pro-apoptotic GDAP1L1 and are mitigated by pro-apoptotic Gm41664. Our findings support the idea that miR-150 contributes significantly to β1AR/β-arrestin-mediated cardioprotection by regulating unique ncRNA and gene signatures in CMs.
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DOI：
10.1161/circheartfailure.121.008686
发表时间：
2022-04
期刊：
Circulation. Heart failure
影响因子：
--
作者：
Aonuma T;Moukette B;Kawaguchi S;Barupala NP;Sepúlveda MN;Frick K;Tang Y;Guglin M;Raman SV;Cai C;Liangpunsakul S;Nakagawa S;Kim IM
通讯作者：
Kim IM
DOI：
10.1016/j.omtn.2017.06.005
发表时间：
2017-09-15
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Chakraborty C;Sharma AR;Sharma G;Doss CGP;Lee SS
通讯作者：
Lee SS
影响因子：
5.6
作者：
Alalaiwe A;Chen CY;Chang ZY;Sung JT;Chuang SY;Fang JY
通讯作者：
Fang JY
影响因子：
--
作者：
Devaux, Yvan;Vausort, Melanie;Squire, Iain B.
通讯作者：
Squire, Iain B.
影响因子：
11.1
作者：
Hsiao J;Yuan TY;Tsai MS;Lu CY;Lin YC;Lee ML;Lin SW;Chang FC;Liu Pimentel H;Olive C;Coito C;Shen G;Young M;Thorne T;Lawrence M;Magistri M;Faghihi MA;Khorkova O;Wahlestedt C
通讯作者：
Wahlestedt C