Insulin-like growth factor-1 preconditioning accentuates intrinsic survival mechanism in stem cells to resist ischemic injury by orchestrating protein kinase Cα-Erk1/2 activation

Gang Lu, Muhammad Ashraf, Khawaja Husnain Haider

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Aims: To test our hypothesis that the intrinsic molecular mechanism in stem cells for adaptation to ischemia is accentuated by preconditioning with insulin-like growth factor (IGF-1). Results: Bone marrow Sca-1 + cells were exposed to oxygen and glucose deprivation (OGD) for up to 12 h. Erk1/2 was activated in Sca-1 + cells under OGD which was blocked by MEK inhibitor (PD98059) and resulted in accelerated cell death. Moreover, elevated intracellular calcium with concomitant activation of protein kinase C (PKC) was observed under OGD. Pretreatment with nifedipine or dantrolene reduced cellular calcium, abrogated PKC and Erk1/2 activation, and increased cytotoxicity. Treatment with phorbol 12-myristate 13-acetate (PMA) for 30 min (short-term) activated Erk1/2, whereas 12 h (long-term) PMA treatment abrogated PKCα, reduced Erk1/2 activation and significantly increased cell death under OGD. These results were confirmed by loss-of-function studies using PKCα and Erk1/2 specific small interfering RNA. Gain-of-function studies with PKCα plasmid transfection improved cell survival under OGD. Preconditioning with 100 nM IGF-1 accentuated the intrinsic mechanism of resistance of the cells to ischemia via Erk1/2 activation and improved their survival under OGD as well as post-transplantation in an experimentally infarcted heart. Innovation: Strategies to target intrinsic survival mechanism in stem cells by growth factor preconditioning to enhance their survival via activation of PKCα and Erk1/2 are innovative. Conclusions: Intracellular calcium elevation under OGD activated PKCα and Erk1/2 as a part of the intrinsic prosurvival mechanism that was accentuated during preconditioning with IGF-1 to protect Sca-1 + cells from ischemic injury.

Original languageEnglish (US)
Pages (from-to)217-228
Number of pages12
JournalAntioxidants and Redox Signaling
Volume16
Issue number3
DOIs
Publication statusPublished - Feb 1 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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