Inhibition of miR-25 improves cardiac contractility in the failing heart.
Inhibition of miR-25 improves cardiac contractility in the failing heart.
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心力衰竭的特点是心功能衰弱，最近的临床试验结果表明，通过促进细胞内钙处理来改善心肌细胞的收缩性可能是一种有效的治疗方法。microRNAs （miRs）在心力衰竭中失调，但它们是否控制收缩力或构成治疗靶点仍是推测性的。通过对人类microRNAome的高通量、功能性筛选，我们发现了通过与编码肌浆网钙摄取泵SERCA2a的mRNA相互作用抑制心肌细胞内钙处理的miRs。在测试的875个mir中，miR-25在体外心肌细胞中有效地延迟钙摄取动力学，并且在小鼠和人类心力衰竭中上调。尽管aav9介导的miR-25在体内的过表达会导致收缩功能的显著丧失，但在小鼠模型中，注射针对miR-25的反义寡核苷酸（antagomiR）可显著阻止已建立的心力衰竭，相对于对照antagomiR，可改善心功能和生存率。这些数据表明，内源性miR-25表达的增加有助于心力衰竭期间心功能的下降，并表明它可能是恢复功能的靶向治疗。
Heart failure is characterized by a debilitating decline in cardiac function, and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy. microRNAs (miRs) are dysregulated with heart failure but whether they control contractility or constitute therapeutic targets remain speculative. Using high throughput, functional screening of the human microRNAome, we identified miRs that suppress intracellular calcium handling in heart muscle by interacting with mRNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a. Of 875 miRs tested, miR-25 potently delayed calcium uptake kinetics in cardiomyocytes in vitro and was upregulated in heart failure, both in mice and humans. Whereas AAV9-mediated overexpression of miR-25 in vivo resulted in a significant loss of contractile function, injection of an antisense oligonucleotide (antagomiR) against miR-25 dramatically halted established heart failure in a mouse model, improving cardiac function and survival relative to a control antagomiR. These data reveal that increased expression of endogenous miR-25 contributes to declining cardiac function during heart failure and suggests that it might be targeted therapeutically to restore function.
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影响因子：
64.8
作者：
Kho, Changwon;Lee, Ahyoung;Jeong, Dongtak;Oh, Jae Gyun;Chaanine, Antoine H.;Kizana, Eddy;Park, Woo Jin;Hajjar, Roger J.
通讯作者：
Hajjar, Roger J.
影响因子：
37.8
作者：
Gurha P;Abreu-Goodger C;Wang T;Ramirez MO;Drumond AL;van Dongen S;Chen Y;Bartonicek N;Enright AJ;Lee B;Kelm RJ Jr;Reddy AK;Taffet GE;Bradley A;Wehrens XH;Entman ML;Rodriguez A
通讯作者：
Rodriguez A
影响因子：
4
作者：
Lemons D;Maurya MR;Subramaniam S;Mercola M
通讯作者：
Mercola M
影响因子：
37.8
作者：
Jessup M;Greenberg B;Mancini D;Cappola T;Pauly DF;Jaski B;Yaroshinsky A;Zsebo KM;Dittrich H;Hajjar RJ;Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators
通讯作者：
Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators
影响因子：
64.5
作者：
Helwak A;Kudla G;Dudnakova T;Tollervey D
通讯作者：
Tollervey D