title: Preconditioning by phosphodiesterase-5 inhibition improves therapeutic efficacy of adipose-derived stem cells following myocardial infarction in mice.
abstract: The rationale of this article is enhancing the therapeutic potential of stem cells in ischemic microenvironments by novel preconditioning strategies is critical for improving cellular therapy. We tested the hypothesis that inhibition of phosphodiesterase-5 (PDE-5) with sildenafil (Viagra) or knockdown with a silencing vector in adipose-derived stem cells (ASCs) would improve their survival and enhance cardiac function following myocardial implantation in vivo. ASCs were treated with sildenafil or PDE-5 silencing vector short hairpin RNA (shRNA(PDE-5)) and subjected to simulated ischemia/reoxygenation in vitro. Both sildenafil and shRNA(PDE-5) significantly improved viability, decreased necrosis, apoptosis, and enhanced the release of growth factors, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), and insulin-like growth factor. Inhibition of protein kinase G reversed these effects. To show the beneficial effect of preconditioned ASCs in vivo, adult male CD-1 mice underwent myocardial infarction. Preconditioned ASCs (4 × 10(5)) were directly injected intramyocardially. Preconditioned ASC-treated hearts showed consistently superior cardiac function when compared with nonpreconditioned ASCs after 4 weeks of treatment. This was associated with significantly reduced fibrosis, increased vascular density, and decreased resident myocyte apoptosis when compared with mice receiving nonpreconditioned ASCs. VEGF, b-FGF, and Angiopoietin-1 were also significantly elevated 4 weeks after cell therapy with preconditioned ASCs. We conclude that preconditioning by inhibition of PDE-5 can be a powerful novel approach to improve stem cell therapy following myocardial infarction.
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Hoke
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: Anindita
authors.initials: A
authors.lastname: Das
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D017209:Apoptosis; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003331:Coronary Vessels / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis / Q000517:prevention & control; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D000068677:Sildenafil Citrate; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002316:Cardiotonic Agents; D036341:Intercellular Signaling Peptides and Proteins; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D017869:Cyclic GMP-Dependent Protein Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP