Preconditioning by phosphodiesterase-5 inhibition improves therapeutic efficacy of adipose-derived stem cells following myocardial infarction in mice

Nicholas N. Hoke, Fadi N. Salloum, David A Kass, Anindita Das, Rakesh C. Kukreja

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)326-335
Number of pages10
JournalStem Cells
Volume30
Issue number2
DOIs
StatePublished - Feb 2012

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Type 5 Cyclic Nucleotide Phosphodiesterases
Stem Cells
Myocardial Infarction
Small Interfering RNA
Therapeutics
Fibroblast Growth Factor 2
Cell- and Tissue-Based Therapy
Vascular Endothelial Growth Factor A
Angiopoietin-1
Apoptosis
Fibroblast Growth Factor 1
Cyclic GMP-Dependent Protein Kinases
Somatomedins
Muscle Cells
Blood Vessels
Intercellular Signaling Peptides and Proteins
Fibrosis
Necrosis
Ischemia

Keywords

  • Adipose-derived stem cells
  • Angiogenesis
  • Echocardiography
  • Myocardial infarction
  • Paracrine factors

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Preconditioning by phosphodiesterase-5 inhibition improves therapeutic efficacy of adipose-derived stem cells following myocardial infarction in mice. / Hoke, Nicholas N.; Salloum, Fadi N.; Kass, David A; Das, Anindita; Kukreja, Rakesh C.

In: Stem Cells, Vol. 30, No. 2, 02.2012, p. 326-335.

Research output: Contribution to journalArticle

Hoke, Nicholas N. ; Salloum, Fadi N. ; Kass, David A ; Das, Anindita ; Kukreja, Rakesh C. / Preconditioning by phosphodiesterase-5 inhibition improves therapeutic efficacy of adipose-derived stem cells following myocardial infarction in mice. In: Stem Cells. 2012 ; Vol. 30, No. 2. pp. 326-335.
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