Hyperinsulinemia enhances transcriptional activity of nuclear factor-κB induced by angiotensin II, hyperglycemia, and advanced glycosylation end products in vascular smooth muscle cells

Inga Golovchenko, Marc L. Goalstone, Peter Watson, Michael Brownlee, Boris Draznin

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

Pathogenesis of macrovascular complications of diabetes may involve an activation of the transcription factor nuclear factor-κB (NF-κB) by hyperglycemia and advanced glycosylation end products (AGEs). Activation of NF-κB is believed to be dependent on activation of the Rho family of GTPases. Although the precise mechanism of the Rho-mediated action is not completely understood, posttranslational modification of the Rho proteins by geranylgeranylation is required for their subsequent activation. We observed that in cultured vascular smooth muscle cells (VSMCs), insulin stimulated the activity of geranylgeranyltransferase (GGTase) I and increased the amounts of geranylgeranylated Rho-A from 47% to 60% (P<0.05). GGTI-286, an inhibitor of GGTase I, blocked both effects of insulin. Increased availability of prenylated Rho-A significantly augmented the abilities of angiotensin II (Ang II), hyperglycemia, and AGEs to activate NF-κB, as measured by NF-κB response-element luciferase reporter activity. Preincubations of VSMCs with insulin for 24 hours doubled NF-κB transactivation by Ang II, hyperglycemia, and AGEs. This priming effect of insulin was completely inhibited by GGTI-286. We demonstrate for the first time, to our knowledge, that insulin potentiates NF-κB-dependent transcriptional activity induced by hyperglycemia, AGEs, and Ang II in VSMCs by increasing the activity of GGTase I and the availability of geranylgeranylated Rho-A.

Original languageEnglish (US)
Pages (from-to)746-752
Number of pages7
JournalCirculation research
Volume87
Issue number9
DOIs
Publication statusPublished - Oct 27 2000

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Keywords

  • Angiotensin II
  • Hyperglycemia
  • Hyperinsulinemia
  • Muscle, smooth, vascular
  • Nuclear factor-κB

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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