MicroRNA-21 is a key determinant in IL-11/Stat3 anti-apoptotic signalling pathway in preconditioning of skeletal myoblasts
MicroRNA-21 is a key determinant in IL-11/Stat3 anti-apoptotic signalling pathway in preconditioning of skeletal myoblasts
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DOI：
10.1093/cvr/cvq151
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发表时间：
2010-10-01
影响因子：
10.8
通讯作者：
Ashraf, Muhammad
中科院分区：
文献类型：
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作者：
Haider, Khawaja Husnain;Idris, Niagara Muhammad;Ashraf, Muhammad
我们之前的研究表明，干细胞和祖细胞的预处理促进了它们在梗死心脏植入后的存活。本研究旨在(i)描述microRNA-21 （miR-21）在骨骼肌母细胞（MY）预处理过程中在白细胞介素-11 （IL-11）信号传导中的作用，（ii）研究预处理后的MY （(MY)-M-PC）在梗死心脏移植后的长期命运。我们报道，用二氮氧化物对MY进行药理学预处理显示IL-11的强烈表达和细胞外信号调节激酶1/2 （Erk1/2）和信号转导和转录激活因子3 （Stat3）的激活，同时miR-21升高。这些分子事件改善了(MY)-M-PC在体外氧化应激下的细胞保护作用，这种保护作用被il -11特异性siRNA、Erk1/2阻滞剂或anti-miR-21预处理(MY)-M-PC所破坏。在雌性大鼠急性心肌梗死心脏模型中进行sry基因检测的体内研究显示，雄性供体(MY)-M-PC在移植后4天和7天的存活率提高了两倍。移植后4个月确定移植细胞的长期命运。免疫组织学研究显示，与非pcmy相比，(MY)-M-PC改善了心脏的血管生成反应，这从每表面积血管数量（0.155 mm(2)）和(MY)-M-PC在心脏的肌源性分化中可以明显看出。（MY）- m - pc处理的动物的心肌收缩性指标包括射血分数和分数缩短均有显著改善。miR-21是MY预处理过程中IL-11下游Erk1/2-Stat3信号传导的关键调节因子。（MY）-M-PC的治疗效果稳定并持续到观察4个月。
We have previously shown that preconditioning of stem and progenitor cells promotes their survival post-engraftment in the infarcted heart. The present study was designed to (i) delineate the role of microRNA-21 (miR-21) in interleukin-11 (IL-11) signalling during preconditioning of skeletal myoblasts (MY) and (ii) study the long-term fate of preconditioned MY ((MY)-M-PC) post-transplantation in the infarcted heart.We report that pharmacological preconditioning of MY with diazoxide showed robust expression of IL-11 and activation of extracellular signal-regulated kinase 1/2 (Erk1/2) and signal transducers and activators of transcription-3 (Stat3) with concomitantly increased miR-21. These molecular events improved cytoprotection of (MY)-M-PC under oxidant stress in vitro which was compromised by pre-treatment of (MY)-M-PC with IL-11-specific siRNA, Erk1/2 blocker, or anti-miR-21. In vivo studies for sry-gene detection in a female rat heart model of acute myocardial infarction showed two-fold higher survival of male donor (MY)-M-PC 4 and 7 days post-engraftment. Long-term fate of the engrafted cells was determined at 4 months after transplantation. Immunohistological studies revealed that in comparison with non-PCMY, (MY)-M-PC improved angiogenic response in the heart which was evident from a higher number of blood vessels per surface area (0.155 mm(2)) and myogenic differentiation of (MY)-M-PC in the heart. Indices of myocardial contractility including ejection fraction and fractional shortening showed significant improvement in (MY)-M-PC-treated animals.miR-21 is a key regulator of Erk1/2-Stat3 signalling downstream of IL-11 during preconditioning of MY. The therapeutic benefits of (MY)-M-PC were stable and persisted until 4 months of observation.