Selective inhibition of inositol hexakisphosphate kinases (IP6Ks) enhances mesenchymal stem cell engraftment and improves therapeutic efficacy for myocardial infarction.

Abstract

5-Diphosphoinositol pentakisphosphate (IP7), formed by a family of inositol hexakisphosphate kinases (IP6Ks), has been demonstrated to be a physiologic inhibitor of Akt. IP6K inhibition may increase Akt activation in mesenchymal stem cells (MSCs), resulting in enhanced cardiac protective effect after transplantation. The aim of this study was to investigate the role of IP6Ks for improving MSCs' functional survival and cardiac protective effect after transplantation into infarcted mice hearts. Bone marrow-derived mesenchymal stem cells, isolated from dual-reporter firefly luciferase and enhanced green fluorescent protein positive (Fluc(+)-eGFP(+)) transgenic mice, were preconditioned with IP6Ks inhibitor TNP (0.5, 1, 5, and 10 μmol/L) for 2 h followed by 6 h of hypoxia and serum deprivation (H/SD) injury. TNP concentration dependently significantly decreased IP7 production with increased Akt phosphorylation. Moreover, TNP at 10 μmol/L significantly improved the viability and enhanced the paracrine effect of MSCs after H/SD. Furthermore, MSCs were transplanted into infarcted hearts with or without selective IP6Ks inhibition. Longitudinal in vivo bioluminescence imaging and immunofluorescent staining revealed that TNP pretreatment enhanced the survival of engrafted MSCs, which promoted the anti-apoptotic and pro-angiogenic efficacy of MSCs in vivo. Furthermore, MSC therapy with IP6Ks inhibition significantly decreased fibrosis and preserved heart function. This study demonstrates that inhibition of IP6Ks promotes MSCs engraftment and paracrine effect in infarcted hearts at least in part by down-regulating IP7 production and enhancing Akt activation, which might contribute to the preservation of myocardial function after MI.

• Authors: Zheng Zhang, Dong Liang, Xue Gao, Chuanxu Zhao, Xing Qin, Yong Xu, Tao Su, Dongdong Sun, Weijie Li, Haichang Wang, Bing Liu, Feng Cao
• Journal: Basic research in cardiology (Basic Res Cardiol) Vol. 109 Issue 4 Pg. 417 (Jul 2014) ISSN: 1435-1803 [Electronic] Germany
• PMID: 24847908 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inositol Phosphates
• Protein Kinase Inhibitors
• Purines
• enhanced green fluorescent protein
• Green Fluorescent Proteins
• Luciferases, Firefly
• Proto-Oncogene Proteins c-akt
• Phosphotransferases (Phosphate Group Acceptor)
• inositol hexakisphosphate kinase

Topics

• Animals
• Apoptosis (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme Activation
• Fibrosis
• Genes, Reporter
• Graft Survival (drug effects)
• Green Fluorescent Proteins (biosynthesis, genetics)
• Inositol Phosphates (metabolism)
• Luciferases, Firefly (biosynthesis, genetics)
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (drug effects, enzymology)
• Mice, Inbred C57BL
• Mice, Transgenic
• Myocardial Infarction (enzymology, pathology, physiopathology, surgery)
• Myocardium (enzymology, pathology)
• Neovascularization, Physiologic (drug effects)
• Phosphotransferases (Phosphate Group Acceptor) (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Purines (pharmacology)
• Recovery of Function
• Signal Transduction (drug effects)
• Time Factors
• Ventricular Function, Left (drug effects)