Evidence that insulin-like growth factor-1 requires protein kinase C-ε, PI3-kinase and mitogen-activated protein kinase pathways to protect human vascular smooth muscle cells from apoptosis

Todd R. Allen, Kristopher D. Krueger, William J. Hunter, Devendra K. Agrawal

    Research output: Contribution to journalArticlepeer-review

    41 Scopus citations

    Abstract

    Insulin-like growth factor (IGF)-1 has been implicated in the development of occlusive vascular lesions. Although its role in vascular smooth muscle cell (VSMC) growth and migration are fairly well characterized, anti-apoptotic signals of IGF-1 in human VSMC remain largely unknown. In this study, we examined IGF-1 signals that protect human and rat VSMC from staurosporine (STAU)- and c-myc- induced apoptosis, respectively. Treatment with STAU resulted in apoptotic DNA fragmentation, phosphatidylserine externalization and cell shrinkage, but only occasional VSMC 'blebbing'. STAU-induced death and IGF-1-mediated survival were concentration dependent, while time-lapse video microscopy showed that IGF-1 inhibited c-myc-induced apoptosis by 90%. Pretreatment with mitogen-activated protein kinase/extracellular signal regulated kinase kinase (MEK) inhibitors UO126 and PD098059, or with the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin, reversed IGF-1-mediated human VSMC survival by 25-27% and 66%, respectively. Translocation studies showed that IGF-1 activated protein kinase C (PKC)-ε, but not PKC-α or PKC-δ, even in the presence of STAU, while pharmacological PKC inhibition (Ro-318220 or Go6976) implicated PKC-ζ or a novel PKC isozyme in IGF-1-mediated survival. Transient expression of activated PKC-ε but not activated PKC-ζ decreased myc-induced apoptosis in rat VSMC. In human VSMC, antisense oligodeoxynucleotides to PKC-ε partially reversed IGF-1-induced survival. In addition, IGF-1 elicited a mild but sustained activation of extracellular signal regulated kinase (ERK)1/2 in human VSMC that was abolished after 1 h in the presence of STAU. PKC downregulation reversed both IGF-1- and PMA-induced ERK activity, but platelet-derived growth factor (PDGF)-induced activity was unchanged. These results indicate for the first time that IGF-1 can protect human VSMC via multiple signals, including PKC-ε, PI3-K and mitogen-activated protein kinase pathways.

    Original languageEnglish
    Pages (from-to)651-667
    Number of pages17
    JournalImmunology and Cell Biology
    Volume83
    Issue number6
    DOIs
    StatePublished - Dec 2005

    All Science Journal Classification (ASJC) codes

    • Immunology
    • Clinical Biochemistry
    • Cell Biology

    Fingerprint

    Dive into the research topics of 'Evidence that insulin-like growth factor-1 requires protein kinase C-ε, PI3-kinase and mitogen-activated protein kinase pathways to protect human vascular smooth muscle cells from apoptosis'. Together they form a unique fingerprint.

    Cite this