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

Autor: Muhammad Ashraf, Ibrahim Elmadbouh
Rok vydání: 2017
Předmět:
0301 basic medicine
MAPK/ERK pathway
Transplantation Conditioning
Physiology
Phosphodiesterase Inhibitors
111In‐oxine imaging
Drug Evaluation
Preclinical
Myocardial Infarction
myelo‐ablation
030204 cardiovascular system & hematology
Pharmacology
Tadalafil
0302 clinical medicine
Cell Movement
Cells
Cultured
Original Research
Ventricular Remodeling
stem cell survival
Graft Survival
Heart
Echocardiography
Female
medicine.drug
Cardiac function curve
Cardiovascular Conditions
Disorders and Treatments
medicine.medical_specialty
Cell Survival
Bone Marrow Cells
Mesenchymal Stem Cell Transplantation
03 medical and health sciences
Physiology (medical)
Spect imaging
medicine
Animals
Ventricular remodeling
business.industry
Mesenchymal stem cell
Mesenchymal Stem Cells
pharmacological preconditioning
medicine.disease
Rats
Inbred F344
Surgery
Mice
Inbred C57BL
Cellular and Molecular Physiology
030104 developmental biology
Apoptosis
Cytoprotection
business
Homing (hematopoietic)
Zdroj: Physiological Reports
ISSN: 2051-817X
Popis: 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.
Databáze: OpenAIRE
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