Tadalafil, a long acting phosphodiesterase inhibitor, promotes bone marrow stem cell survival and their homing into ischemic myocardium for cardiac repair.
Tadalafil, a long acting phosphodiesterase inhibitor, promotes bone marrow stem cell survival and their homing into ischemic myocardium for cardiac repair.
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DOI：
10.14814/phy2.13480
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发表时间：
2017-11
影响因子：
2.5
通讯作者：
Ashraf M
中科院分区：
文献类型：
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作者：
Elmadbouh I;Ashraf M
目的是在分子水平上评价他达拉非介导的对骨髓间充质干细胞（MSC）存活及其归巢至梗死心脏以促进心脏修复和改善功能的影响。在他达拉非处理2 h之前，用PKG、MAPK、FasL、一氧化氮合酶（NOS）（L-NAME）、CXCR 4（AMD 3100）或miR-21抑制剂（+/−荧光素酶构建+/−Fas）体外预处理MSC。然后使这些MSC经受H2 O2应激以评估它们的损伤。对大鼠进行急性心肌梗死（AMI），然后向梗死和非梗死区域注射生理盐水或1.5 x 106 MSC处理的±他达拉非。在另一组中，在骨髓消融后1个月的大鼠中进行AMI，并腹腔内（IP）注射他达拉非± AMD 3100或L-NAME 5天。此外，在另一组中，AMI小鼠在静脉注射111 In ‐oxine‐ MSC之前用IP ±他达拉非处理，随后进行CT/SPECT成像以定位动员的MSC。超声心动图评价心功能。通过分子生物测定法分析MSC和心脏提取物。他达拉非处理的MSC的cGMP、NOS、SDF-1α、p-VASP、p-Erk 1/2、p-STAT 3、p-Akt、PKG 1和Bcl-xl表达较高; PKG 1、MAPK、NOS或FasL抑制剂可降低这些分子的表达。他达拉非通过增加miR-21表达抑制细胞凋亡，并通过抑制Fas（通过PKG 1、MAPK或miR-21抑制剂恢复）改善细胞存活。在体内，与对照组相比，他达拉非治疗的AMI动物的心脏功能、移植细胞存活率、MSC动员和归巢得到改善。结论：他达拉非通过上调miR-21依赖性Fas抑制延长MSC存活，并增加MSC动员及其归巢至梗死心肌，从而改善心脏修复和功能。
The aim was to evaluate the tadalafil‐mediated effects at molecular level on bone marrow‐derived mesenchymal stem cells (MSCs) survival and their homing into the infarcted hearts to promote cardiac repair and improve function. MSCs were pretreated in vitro with inhibitors of PKG, MAPK, FasL, nitric oxide synthase (NOS) (L‐NAME), CXCR4 (AMD3100), or miR‐21 inhibitors (+/−luciferase construction +/−Fas) prior to tadalafil treatment for 2 h. These MSCs were then subjected to H2O2 stress to assess their injury. Rats were subjected to acute myocardial infarction (AMI), and then followed by injection of saline or 1.5 x 106 MSCs‐treated ± tadalafil into infarcted and peri‐infarcted area. In another group, AMI was performed in 1‐month post‐myelo‐ablated rats and were injected intraperitoneally (IP) with tadalafil ± AMD3100 or L‐NAME for 5 days. Also, in another group, AMI mice were treated with IP ± tadalafil before intravenous injection with 111In‐oxine‐MSCs followed by CT/SPECT imaging to locate mobilized MSCs. Cardiac function was assessed by echocardiography. MSCs and heart extracts were analyzed by molecular bioassays. Tadalafil‐treated MSCs had higher expression of cGMP, NOS, SDF‐1α, p‐VASP, p‐Erk1/2, p‐STAT3, p‐Akt, PKG1 and Bcl‐xl; expression of these molecules was reduced with PKG1, MAPK, NOS or FasL inhibitors. Tadalafil inhibited apoptosis through increased miR‐21 expression and improved cell survival by inhibiting Fas (restored by PKG1, MAPK or miR‐21 inhibitors). In vivo, heart function, grafted cell survival, MSCs mobilization and homing were improved in tadalafil‐treated AMI animals versus controls. Conclusions: Tadalafil prolonged MSCs survival via up‐regulation of miR‐21 dependent suppression of Fas, and increased MSCs mobilization and their homing into infarcted myocardium resulting in improved cardiac repair and function.