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Hypoxia‐induced ARHGAP26 deficiency inhibits the proliferation and migration of human ductus arteriosus smooth muscle cell through activating RhoA‐ROCK‐PTEN pathway
Author(s) -
Li Minghui,
Ye Lincai,
Ye Xiuxia,
Wang Shoubao,
Zhang Haibo,
Liu Jinfen,
Hong Haifa
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.28294
Subject(s) - rhoa , pten , tensin , rock1 , myosin light chain phosphatase , microbiology and biotechnology , rho associated protein kinase , rock2 , cancer research , biology , cell growth , gtpase , cell migration , signal transduction , cell , pi3k/akt/mtor pathway , biochemistry
The Rho family plays crucial roles in O 2 ‐induced vasoconstriction, cell proliferation, and migration. Rho GTPase‐activating protein 26 (ARHGAP26) is a GTPase‐activating protein for the small GTPases of the Rho family. Our previous studies have demonstrated that ARHGAP26 expression was significantly downregulated in patent human ductus arteriosus (DA) tissue. However, its role underlying the maintenance of DA patency is unclear. In this study, patent (fetal) and constricted (newborn) mouse DA tissues were harvested to confirm the differences in the levels of expression of ARHGAP26. Human DA smooth muscle cells (DASMCs) were isolated and cultured in vitro and used to test the function of ARHGAP26. The expression of ARHGAP26 was significantly lower in patent (fetal) than constricted (newborn) mouse DA. ARHGAP26‐knocked‐down human DASMCs showed reduced proliferation and migration, which are both crucial to anatomic closure of DA. Moreover, after culturing under hypoxic conditions, the expression of ARHGAP26 in human DASMCs was significantly lower and hypoxia‐induced ARHGAP26 deficiency activated the phosphorylation level of phosphatase and tensin homolog (PTEN) in DASMCs by mediating the activity of RhoA and RhoA‐associated kinase 1 (ROCK1). Use of Y27632, an inhibitor of ROCK which further reduces the phospholipid activity of PTEN can reverse the inhibitory effect of PTEN on the proliferation and migration of human DASMCs. This provides insight into the molecular regulation of the RhoA‐ROCK‐PTEN pathway in DA smooth muscle cells, which may be a suitable therapeutic target or diagnostic biomarker for perinatal DA tone management.