Cardiac telocytes inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted cdip1 silencing to improve angiogenesis following myocardial infarction.
Cardiac telocytes inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted cdip1 silencing to improve angiogenesis following myocardial infarction.
复制标题
心肌细胞通过外泌体 miRNA-21-5p 靶向 cdip1 沉默抑制心脏微血管内皮细胞凋亡，改善心肌梗死后的血管生成
作者：
Liao Z;Chen Y;Duan C;Zhu K;Huang R;Zhao H;Hintze M;Pu Q;Yuan Z;Lv L;Chen H;Lai B;Feng S;Qi X;Cai D
促进缺血心肌血管生成是心肌梗死(MI)后修复和再生心肌的重要策略。目前，帮助内皮细胞存活、避免缺血心肌细胞凋亡和实现长期心脏血管生成的有效方法仍在探索之中。在这里，我们研究了心肌梗死期间心脏端粒细胞(CT)-内皮细胞通讯是否抑制了细胞凋亡并促进了内皮细胞的存活以促进心脏血管生成。方法：从CT条件培养液中分离出CT外切体，用小RNA测序鉴定其miRNA图谱。采用左冠状动脉前降支结扎(LAD)法制备大鼠急性心肌梗死(MI)模型，观察心肌梗死面积和纤维化程度、血管生成和细胞凋亡的免疫组化染色及超声心动图检查，评价治疗效果。应用细胞学和分子生物学技术对CT外切体或CT外切体miRNA-21-5p处理的心肌微血管内皮细胞(CMECs)和LAD-MI模型进行了体内外评价。结果：CTS通过CT外切体强大的旁分泌作用，抑制心肌内皮细胞的凋亡和存活，促进心脏血管生成，从而发挥对MI的治疗作用。揭示了CTS的一种新的机制，即CT-内皮细胞通讯抑制细胞凋亡，促进病理生理心肌内皮细胞的存活。CT外体miRNA-21-5p靶向并沉默细胞死亡诱导P53靶基因1(Cdip1)，下调激活的caspase-3，从而抑制缺血和缺氧条件下受体内皮细胞的凋亡，促进心肌梗死后血管生成和再生。结论：本研究首次表明CTs通过外体miRNA-21-5p靶向Cdip1沉默来抑制心肌微血管内皮细胞的凋亡，从而促进心肌梗死后的血管生成。相信这些新的发现和细胞和分子机制的发现将为为受损心肌的功能和结构再生量身定做新的心脏细胞疗法和无细胞疗法提供新的机会。
Promotion of cardiac angiogenesis in ischemic myocardium is a critical strategy for repairing and regenerating the myocardium after myocardial infarction (MI). Currently, effective methods to aid in the survival of endothelial cells, to avoid apoptosis in ischemic myocardium and to achieve long-term cardiac angiogenesis are still being pursued. Here, we investigated whether cardiac telocyte (CT)-endothelial cell communication suppresses apoptosis and promotes the survival of endothelial cells to facilitate cardiac angiogenesis during MI. Methods: CT exosomes were isolated from CT conditioned medium, and their miRNA profile was characterized by small RNA sequencing. A rat model of left anterior descending coronary artery ligation (LAD)-mediated MI was assessed with histology for infarct size and fibrosis, immunostaining for angiogenesis and cell apoptosis and echocardiography to evaluate the therapeutic effects. Cardiac microvascular endothelial cells (CMECs) and the LAD-MI model treated with CT exosomes or CT exosomal miRNA-21-5p in vitro and in vivo were assessed with cellular and molecular techniques to demonstrate the underlying mechanism. Results: CTs exert therapeutic effects on MI via the potent paracrine effects of CT exosomes to facilitate the inhibition of apoptosis and survival of CMECs and promote cardiac angiogenesis. A novel mechanism of CTs is revealed, in which CT-endothelial cell communication suppresses apoptosis and promotes the survival of endothelial cells in the pathophysiological myocardium. CT exosomal miRNA-21-5p targeted and silenced the cell death inducing p53 target 1 (Cdip1) gene and thus down-regulated the activated caspase-3, which then inhibited the apoptosis of recipient endothelial cells under ischemic and hypoxic conditions, facilitating angiogenesis and regeneration following MI. Conclusions: The present study is the first to show that CTs inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted Cdip1 silencing to improve angiogenesis in myocardial infarction. It is believed that these novel findings and the discovery of cellular and molecular mechanisms will provide new opportunities to tailor novel cardiac cell therapies and cell-free therapies for the functional and structural regeneration of the injured myocardium.