Myocardial injection of apelin-overexpressing bone marrow cells improves cardiac repair via upregulation of Sirt3 after myocardial infarction.
Myocardial injection of apelin-overexpressing bone marrow cells improves cardiac repair via upregulation of Sirt3 after myocardial infarction.
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DOI：
10.1371/journal.pone.0071041
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chen JX
中科院分区：
文献类型：
--
作者：
Li L;Zeng H;Hou X;He X;Chen JX
我们以前的研究表明，apelin治疗增加了骨髓细胞（BMC）的招募，并促进心肌梗死（MI）后的心脏修复。本研究的目的是调查是否在BMC中过表达爱帕琳改善细胞治疗并加速MI后小鼠的心脏修复和功能恢复。通过冠状动脉结扎造成小鼠心肌梗死，手术后立即将过表达apelin的BMCs（apelin-BMCs）或GFP（GFP-BMCs）注射到缺血区域。在体外，将培养的BMC暴露于爱帕琳导致SDF-1 α和CXCR 4表达逐渐增加。与GFP-BMC处理的MI后小鼠相比，在MI后小鼠中心肌内递送apelin-BMC导致注射区域中APJ+/c-kit+/Sca 1+细胞的数量显著增加。用apelin-BMCs治疗增加MI后小鼠中VEGF、Ang-1和Tie-2的表达。Apelin-BMC治疗还显著增加MI后小鼠中的血管生成并减弱心脏纤维化形成。最重要的是，用爱帕琳-BMC治疗显著改善了MI后小鼠的左心室（LV）收缩功能。在机制上，Apelin-BMC处理导致Sirtuin 3（Sirt 3）表达的显著增加和活性氧（ROS）形成的减少。用apelin处理培养的BMC也增加Notch 3表达和Akt磷酸化。Apelin处理进一步减弱了应激诱导的细胞凋亡，而Sirt 3的敲除消除了apelin在培养的BMCs中的抗凋亡作用。此外，敲除Sirt 3显著减弱了MI后小鼠中apelin-BMCs诱导的VEGF表达和血管生成。Sirt 3的敲除进一步减弱了心肌梗死后小鼠中apelin-BMC介导的心脏修复和收缩功能恢复的改善。这些数据表明，爱帕琳改善了BMC治疗对MI后小鼠心脏修复和收缩功能的影响。Sirt 3的上调可能有助于apelin-BMCs治疗的保护作用。
Our previous study shows that treatment with apelin increases bone marrow cells (BMCs) recruitment and promotes cardiac repair after myocardial infarction (MI). The objective of this study was to investigate whether overexpression of apelin in BMCs improved cell therapy and accelerated cardiac repair and functional recovery in post-MI mice. Mouse myocardial infarction was achieved by coronary artery ligation and BMCs overexpressing apelin (apelin-BMCs) or GFP (GFP-BMCs) were injected into ischemic area immediately after surgery. In vitro, exposure of cultured BMCs to apelin led to a gradual increase in SDF-1á and CXCR4 expression. Intramyocardial delivery of apelin-BMCs in post-MI mice resulted in a significant increase number of APJ+/c-kit+/Sca1+ cells in the injected area compared to GFP-BMCs treated post-MI mice. Treatment with apelin-BMCs increased expression of VEGF, Ang-1 and Tie-2 in post-MI mice. Apelin-BMCs treatment also significantly increased angiogenesis and attenuated cardiac fibrosis formation in post-MI mice. Most importantly, treatment with apelin-BMCs significantly improved left ventricular (LV) systolic function in post-MI mice. Mechanistically, Apelin-BMCs treatment led to a significant increase in Sirtuin3 (Sirt3) expression and reduction of reactive oxygen species (ROS) formation. Treatment of cultured BMCs with apelin also increased Notch3 expression and Akt phosphorylation. Apelin treatment further attenuated stress-induced apoptosis whereas knockout of Sirt3 abolished anti-apoptotic effect of apelin in cultured BMCs. Moreover, knockout of Sirt3 significantly attenuated apelin-BMCs-induced VEGF expression and angiogenesis in post-MI mice. Knockout of Sirt3 further blunted apelin-BMCs-mediated improvement of cardiac repair and systolic functional recovery in post-MI mice. These data suggest that apelin improves BMCs therapy on cardiac repair and systolic function in post-MI mice. Upregulation of Sirt3 may contribute to the protective effect of apelin-BMCs therapy.
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