Fatty acids inhibit growth-factor-induced diacylglycerol kinase α activation in vascular smooth-muscle cells

X. Du, Y. Jiang, W. Qian, X. Lu, J. P. Walsh

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

We have previously shown that unsaturated fatty acids amplify platelet-derived-growth-factor (PDGF)-induced protein kinase C (PKC) activation in vascular smooth-muscle cells (VSMCs). Diacylglycerol-induced PKC activation is normally terminated by diacylglycerol kinases (DGKs). We thus hypothesized that fatty acids act by inhibiting a DGK. Fractionation of VSMC extracts demonstrated that the DGK α isoform was the major DGK activity present. PDGF markedly increased the DGK activity of cultured cells. An inhibitor selective for the DGK α isoform, R59949 [3-{2-[4-(bis-(4-fluorophenyl)methylene]-piperidin-1-yl)ethyl}-2,3-dihydro- 2-thioxo-4(1H)-quinazolinone], abolished the growth-factor-induced increase in DGK activity, but had little effect on basal activity. PDGF thus selectively activates DGKα. Epidermal growth factor and α-thrombin stimulated total DGK activity similarly to PDGF. Activation by epidermal growth factor was sensitive to R59949, again suggesting involvement of DGKα. However, the α-thrombin-induced activity was unaffected by this agent. Unsaturated fatty acids inhibited growth-factor-induced DGKα activation, but had no effect on basal activity. Fatty acids also amplified the PDGF-induced increase in cell diacylglycerol content. These results indicate that inhibition of DGKα contributes to fatty-acid-induced amplification of PKC activation. Increased levels of fatty acids in diabetes may thus contribute to chronic PKC activation associated with this disorder.

Original languageEnglish (US)
Pages (from-to)275-282
Number of pages8
JournalBiochemical Journal
Volume357
Issue number1
DOIs
StatePublished - Jul 1 2001

Keywords

  • Diabetes mellitus
  • Non-esterified fatty acids
  • Platelet-derived growth factor
  • Protein kinase C
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Biochemistry

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