Title

Tadalafil, a Phosphodiesterase Inhibitor Protects Stem Cells over Longer Period Against Hypoxia/Reoxygenation Injury Through STAT3/PKG-I Signaling

Authors

Authors

S. Kumar;M. Ashraf

Comments

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Abbreviated Journal Title

Stem Cells Dev.

Keywords

NITRIC-OXIDE SYNTHASE; JAK-STAT PATHWAY; CONSCIOUS RABBITS; LATE-PHASE; INDUCED CARDIOPROTECTION; IN-VIVO; ACTIVATION; PHOSPHORYLATION; SURVIVAL; KINASES; Cell & Tissue Engineering; Hematology; Medicine, Research &; Experimental; Transplantation

Abstract

Pharmacological preconditioning (PC) with tadalafil, a PDE5A inhibitor, enhances protein kinase G-1 (PKG-I) activity, resulting in stem cell survival. Protection by PC had two different phases, early (2 h) and late (24 h). However, the mechanism of protection during these phases remained grossly unknown. Mesenchymal stem cells (MSCs) from adult male Fischer-344 rats were cultured and pretreated with tadalafil (100 mu M) for an hour and subjected to 2 h of hypoxia (1% O-2), followed by reoxygenation (HR: in vitro model mimicking ischemia/reperfusion). We observed (i) increased MSC survival with reduced cell cytotoxicity as revealed by low lactate dehydrogenase release and trypan blue staining, respectively, in tadalafil-treated cells upon HR; (ii) decrease in TUNEL positivity as well as caspase activity; (iii) an increase in pAkt/Akt, iNOS, eNOS, and pGSK3 beta/GSK3 beta during the early protection phase of PC, and this protection seemed to be a spontaneous adaptive response of MSCs against HR and was independent of tadalafil, whereas an increase in Bcl2/Bax was tadalafil dependent; and (iv) during the late phase, we observed phosphorylation of STAT3 at serine727, leading to its entry inside the nucleus and binding onto the promoter of PKG-I by three-fold (P<0.05). In conclusion, an increase in Bcl2/Bax during the early phase and transcriptional upregulation of PKG-I by STAT3 during the late phase were responsible for stem cell protection by tadalafil against ischemic injury.

Journal Title

Stem Cells and Development

Volume

24

Issue/Number

11

Publication Date

1-1-2015

Document Type

Article

Language

English

First Page

1332

Last Page

1341

WOS Identifier

WOS:000354612600006

ISSN

1547-3287

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