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Midkine prevented hypoxic injury of mouse embryonic stem cells through activation of Akt and HIF‐1α via low‐density lipoprotein receptor‐related protein‐1
Author(s) -
Lee Sang Hun,
Suh Han Na,
Lee Yu Jin,
Seo Bit Na,
Ha Jeong Won,
Han Ho Jae
Publication year - 2012
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22897
Subject(s) - protein kinase b , midkine , embryonic stem cell , microbiology and biotechnology , stem cell , hypoxia (environmental) , receptor , ldl receptor , chemistry , cancer research , biology , lipoprotein , signal transduction , endocrinology , biochemistry , growth factor , gene , cholesterol , organic chemistry , oxygen
Stem cell functions are dramatically altered by oxygen in tissue culture, which means the antioxidant/oxidant balance is critical for protection as well as toxicity. This study examined the effect of the heparin‐binding growth factor midkine (MK) on hypoxia‐induced apoptosis and related signal pathways in mouse embryonic stem cells (mESCs). Hypoxia (60 h) increased lactate dehydrogenase release and apoptosis, and reduced cell viability and proliferation. These effects were reversed by MK (100 ng/ml). MK also reversed hypoxia‐induced increases of intracellular reactive oxygen species, c‐Jun N‐terminal kinase (JNK), and p38 mitogen‐activated protein kinase (MAPK) phosphorylation. Blockage of JNK and p38 MAPK using small interference (si)RNAs produced a decrease in apoptosis. A loss of mitochondrial membrane potential, increases of cytochrome c release from mitochondria to cytosol, and cleaved caspase‐3 expression, as well as decreases in cIAP‐2 and Bcl‐2 were also reversed by MK. Hypoxia alone and hypoxia with MK increased low‐density lipoprotein receptor‐related protein‐1 (LRP‐1) mRNA and protein expression. Hypoxia with MK rapidly increased serine/threonine protein kinase (Akt) phosphorylation which reversed by LRP‐1 Ab (0.1 µg/ml) and prolonged heme oxygenase‐1 (HO‐1) expression. In addition, hypoxia with MK increased the expression of hypoxia‐inducible factor‐1α (HIF‐1α). Moreover, inhibition of Akt, HO‐1, and HIF‐1α signaling pathways abolished the MK‐induced blockage of apoptosis. In conclusion, MK partially prevented hypoxic injury of mESCs through activation of Akt, HO‐1, and HIF‐1α via LRP‐1. J. Cell. Physiol. 227: 1731–1739, 2012. © 2011 Wiley Periodicals, Inc.