Phosphodiesterase inhibition with tadalafil provides longer and sustained protection of stem cells

Husnain Kh Haider, Yun Jung Lee, Shujia Jiang, Rafeeq P.H. Ahmed, Mok Ryon, Muhammad Ashraf

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

We hypothesized that inhibition of the cGMP-specific enzyme phosphodiesterase 5A (PDE5A) promoted cGMP/protein kinase G (PKG) activity to condition stem cells for enhanced survival and proliferation. One-time tadalafil treatment (1 μM for 30 min) of mesenchymal stem cells ( TadaMSCs) provided sustained protection of cells for 36 h. Higher cGMP activity with concomitantly increased PKG1 activity was observed in TadaMSCs, which peaked within 12 h after tadalafil treatment. Pretreatment with PKG1 blockers (1 μM KT-5823 or 20 nM K-252a) or transduction with adenoviral PKG1-short-hairpin RNA abolished tadalafil-induced cytoprotection of the cells. A higher proliferation rate was observed in TadaMSCs compared with nontreated MSCs ( ContMSCs). In a rat model of acute myocardial infarction, TadaMSCs transplanted 0 and 24 h after tadalafil treatment showed higher survival compared with ContMSCs on day 2 and day 4 after engraftment. TadaMSCs transplanted 48 h after tadalafil treatment lost their protection on both day 2 and day 4 after engraftment, and their rate of survival was similar to ContMSCs. Reduced terminal dUTP nick end-labeling positivity (P < 0.01 vs. ContMSCs) and higher proliferation of TadaMSCs (P < 0.01 vs. ContMSCs) was observed in the infarcted heart. Fluorescence immunostaining revealed neomyogenesis in both the infarct and peri-infarct areas. Blood vessel density was significantly increased in group 2 compared with group 1. Transthoracic echocardiographic heart function revealed significant preservation of the indexes of left ventricle contractility and attenuation of remodeling in TadaMSC-engrafted animal hearts (group 2) compared with ContMSCs (group 1). PDE5A inhibition using long-acting tadalafil is an innovative approach to promote stem cell survival and proliferation in the infarcted heart.

Original languageEnglish (US)
Pages (from-to)H1395-H1404
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume299
Issue number5
DOIs
StatePublished - Nov 1 2010
Externally publishedYes

Keywords

  • Cytoprotection
  • Phosphodiesterase
  • Preconditioning
  • Stem cells
  • Tadalafil

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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