title: PI3K p110α isoform-dependent Rho GTPase Rac1 activation mediates H2S-promoted endothelial cell migration via actin cytoskeleton reorganization.
abstract: Hydrogen sulfide (H(2)S) is now considered as the third gaseotransmitter, however, the signaling pathways that modulate the biomedical effect of H(2)S on endothelial cells are poorly defined. In the present study, we found in human endothelial cells that H(2)S increased cell migration rates and induced a marked reorganization of the actin cytoskeleton, which was prevented by depletion of Rac1. Pharmacologic inhibiting vascular endothelial growth factor receptor (VEGFR) and phosphoinositide 3-kinase (PI3K) both blunted the activation of Rac1 and the promotion of cell migration induced by H(2)S. Moreover, H(2)S-induced Rac1 activation was selectively dependent on the presence of the PI3K p110α isoform. Activated Rac1 by H(2)S thus in turn resulted in the phosphorylation of the F-actin polymerization modulator, cofilin. Additionally, inhibiting of extracellular signal-regulated kinase (ERK) decreased the augmented cell migration rate by H(2)S, but had no effect on Rac1 activation. These results indicate that Rac1 conveys the H(2)S signal to microfilaments inducing rearrangements of actin cytoskeleton that regulates cell migration. VEGFR-PI3K was found to be upstream pathway of Rac1, while cofilin acted as a downstream effector of Rac1. ERK was also shown to be involved in the action of H(2)S on endothelial cell migration, but independently of Rac1.
authors.affiliation: Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College, Shanghai, China.
authors.forename: Li-Jia
authors.initials: LJ
authors.lastname: Zhang
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Tao
authors.forename: Ming-Jie
authors.initials: MJ
authors.lastname: Wang
authors.forename: Hui-Ming
authors.initials: HM
authors.lastname: Jin
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Zhu
mesh_terms: D000199:Actins / Q000378:metabolism*; D001483:Base Sequence; D002465:Cell Movement / Q000187:drug effects*; D003599:Cytoskeleton / Q000378:metabolism*; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000199:Actins; D017931:DNA Primers; D007527:Isoenzymes; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D020830:rac1 GTP-Binding Protein; D006862:Hydrogen Sulfide