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

20 Citations (Scopus)

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

Fingerprint

Phosphoric Diester Hydrolases
Stem Cells
Type 5 Cyclic Nucleotide Phosphodiesterases
Cytoprotection
Cell Survival
Cell Proliferation
Cyclic GMP-Dependent Protein Kinases
Mesenchymal Stromal Cells
Small Interfering RNA
Heart Ventricles
Blood Vessels
Tadalafil
Fluorescence
Myocardial Infarction
Enzymes

Keywords

  • Cytoprotection
  • Phosphodiesterase
  • Preconditioning
  • Stem cells
  • Tadalafil

ASJC Scopus subject areas

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

Cite this

Phosphodiesterase inhibition with tadalafil provides longer and sustained protection of stem cells. / Haider, Husnain Kh; Lee, Yun Jung; Jiang, Shujia; Ahmed, Rafeeq P.H.; Ryon, Mok; Ashraf, Muhammad.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 299, No. 5, 01.11.2010, p. H1395-H1404.

Research output: Contribution to journalArticle

Haider, Husnain Kh ; Lee, Yun Jung ; Jiang, Shujia ; Ahmed, Rafeeq P.H. ; Ryon, Mok ; Ashraf, Muhammad. / Phosphodiesterase inhibition with tadalafil provides longer and sustained protection of stem cells. In: American Journal of Physiology - Heart and Circulatory Physiology. 2010 ; Vol. 299, No. 5. pp. H1395-H1404.
@article{11bdd1bd981c4ec5b2555673345f8657,
title = "Phosphodiesterase inhibition with tadalafil provides longer and sustained protection of stem cells",
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.",
keywords = "Cytoprotection, Phosphodiesterase, Preconditioning, Stem cells, Tadalafil",
author = "Haider, {Husnain Kh} and Lee, {Yun Jung} and Shujia Jiang and Ahmed, {Rafeeq P.H.} and Mok Ryon and Muhammad Ashraf",
year = "2010",
month = "11",
day = "1",
doi = "10.1152/ajpheart.00437.2010",
language = "English (US)",
volume = "299",
pages = "H1395--H1404",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "5",

}

TY - JOUR

T1 - Phosphodiesterase inhibition with tadalafil provides longer and sustained protection of stem cells

AU - Haider, Husnain Kh

AU - Lee, Yun Jung

AU - Jiang, Shujia

AU - Ahmed, Rafeeq P.H.

AU - Ryon, Mok

AU - Ashraf, Muhammad

PY - 2010/11/1

Y1 - 2010/11/1

N2 - 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.

AB - 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.

KW - Cytoprotection

KW - Phosphodiesterase

KW - Preconditioning

KW - Stem cells

KW - Tadalafil

UR - http://www.scopus.com/inward/record.url?scp=78249259700&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78249259700&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00437.2010

DO - 10.1152/ajpheart.00437.2010

M3 - Article

C2 - 20833962

AN - SCOPUS:78249259700

VL - 299

SP - H1395-H1404

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 5

ER -