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Tadalafil, a long acting phosphodiesterase inhibitor, promotes bone marrow stem cell survival and their homing into ischemic myocardium for cardiac repair.

ABSTRACT: 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-1?, 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.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.

SUBMITTER: Elmadbouh I

PROVIDER: S-EPMC5688776 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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Tadalafil, a long acting phosphodiesterase inhibitor, promotes bone marrow stem cell survival and their homing into ischemic myocardium for cardiac repair.

Elmadbouh Ibrahim I Ashraf Muhammad M

Physiological reports 20171101 21

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 H<sub>2</sub>O<sub>2</s ...[more]

PMID: 29138357

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Project description:RationaleEndothelial progenitor cell (EPC) survival and function in the injured myocardium is adversely influenced by hostile microenvironment such as ischemia, hypoxia, and inflammatory response, thereby compromising full benefits of EPC-mediated myocardial repair.ObjectiveWe hypothesized that interleukin-10 (IL-10) modulates EPC biology leading to enhanced survival and function after transplantation in the ischemic myocardium.Methods and resultsMyocardial infarction (MI)-induced mobilization of bone marrow EPC (Sca-1+Flk1+cells) into the circulation was significantly impaired in IL-10 knockout (KO) mice. Bone marrow transplantation to replace IL-10 KO marrow with wild-type (WT) marrow attenuated these effects. Impaired mobilization was associated with lower stromal cell-derived factor (SDF)-1 expression levels in the myocardium of KO mice. Interestingly, SDF-1 administration reversed mobilization defect in KO mice. In vitro, hypoxia-mediated increases in CXCR4 expression and cell survival were lower in IL-10-deficient EPCs. Furthermore, SDF-1-induced migration of WT EPCs was inhibited by AMD3100, an inhibitor of CXCR4. To further study the effect of IL-10 on in vivo EPC survival and engraftment into vascular structures, GFP-labeled EPC were injected intramyocardially after induction of MI, and the mice were treated with either saline or recombinant IL-10. The IL-10-treated group showed increased retention of transplanted EPCs in the myocardium and was associated with significantly reduced EPC apoptosis after MI. Interestingly, increased EPC retention and their association with the vascular structures was observed in IL-10-treated mice. Increased EPC survival and angiogenesis in the myocardium of IL-10-treated mice corroborated with improved left ventricular function, reduced infarct size, and fibrosis in the myocardium. In vitro, IL-10-induced increase in VEGF expression in WT EPC was abrogated by STAT3 inhibitor, suggesting IL-10 signals through STAT3 activation.ConclusionsTaken together, our studies demonstrate that MI-induced EPC mobilization was impaired in IL-10 KO mice and that IL-10 increases EPC survival and function possibly through activation of STAT3/VEGF signaling cascades, leading to attenuation of MI-induced left ventricular dysfunction and remodeling.

Dataset Information

Tadalafil, a long acting phosphodiesterase inhibitor, promotes bone marrow stem cell survival and their homing into ischemic myocardium for cardiac repair.

Publications

Tadalafil, a long acting phosphodiesterase inhibitor, promotes bone marrow stem cell survival and their homing into ischemic myocardium for cardiac repair.

Similar Datasets

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