TNF alpha inhibits insulin's antiapoptotic signaling in vascular smooth muscle cells

Tumor necrosis factor alpha (TNF alpha) interferes with insulin signaling i n adipose tissue and may promote insulin resistance. Insulin resistance is associated with vascular injury, but little is known about the interaction of TNF alpha and insulin in the vasculature. By activating the Insulin rece ptor (IR) --> IRS-1 --> phosphatidylinositol-3-kinase (PI3K) --> Akt-pathwa y, insulin protects vascular smooth muscle cells (VSMC) from undergoing apo ptosis. We therefore investigated the effect of TNF alpha on insulin's anti apoptotic signaling in rat aortic VSMC. Insulin induced rapid tyrosine-phos phorylation of the IR and IRS-1 and caused a 2.8-fold increase of IRS-1-bou nd PI3K. TNF alpha had no effect on insulin-induced tyrosinephosphorylation of IR or IRS-1, but inhibited insulin-stimulated IRS-1/PI3K-association by 84%. Insulin-induced phosphorylation of Akt downstream of PI3K was inhibit ed by TNF alpha in a similar pattern. We next examined the effect of TNF al pha on insulin's protective actions on H2O2-induced apoptosis. Insulin alon e prevented 72.8% of H2O2-induced apoptosis, which was significantly inhibi ted by TNF alpha. TNF alpha alone did not induce apoptosis. In contrast, TN F alpha had no effect on PDGF-induced antiapoptotic signal transduction via Akt. Thus, TNF alpha selectively interferes with insulin's antiapoptotic s ignaling in VSMC by inhibiting the association of IRS-1/PI3K and the downst ream activation of Akt. (C) 2001 Academic Press.