TY - JOUR
T1 - Tadalafil, a long acting phosphodiesterase inhibitor, promotes bone marrow stem cell survival and their homing into ischemic myocardium for cardiac repair
AU - Elmadbouh, Ibrahim
AU - Ashraf, Muhammad
N1 - Funding Information:
This work was carried out at the University of Cincinnati during senior authors‘ tenure and was supported by NIH Grants R37-HL-074272, HL-095375 and HL-087246 (M. Ashraf).
Publisher Copyright:
© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc.
PY - 2017
Y1 - 2017
N2 - 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 with111In-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.
AB - 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 with111In-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.
KW - In-oxine imaging
KW - myelo-ablation
KW - pharmacological preconditioning
KW - stem cell survival
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U2 - 10.14814/PHY2.13480
DO - 10.14814/PHY2.13480
M3 - Article
C2 - 29138357
AN - SCOPUS:85044620848
SN - 2051-817X
VL - 5
JO - Physiological reports
JF - Physiological reports
IS - 21
M1 - e13480
ER -