Role of calcium-independent phospholipase a2β in high glucose-induced activation of RhoA, Rho Kinase, and CPI-17 in cultured vascular smooth muscle cells and vascular smooth muscle hypercontractility in diabetic animals

Zhongwen Xie, Ming C. Gong, Wen Su, Dongping Xie, John Turk, Zhenheng Guo

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Previous studies suggest that high glucose-induced RhoA/ Rho kinase/CPI-17 activation is involved in diabetes-associated vascular smooth muscle hypercontractility. However, the upstream signaling that links high glucose and RhoA/Rho kinase/ CPI-17 activation is unknown. Here we report that calcium-independent phospholipase A2β (iPLA2β) is required for high glucose-induced RhoA/Rho kinase/CPI-17 activation and thereby contributes to diabetes-associated vascular smooth muscle hypercontractility. We demonstrate that high glucose increases iPLA 2β mRNA, protein, and iPLA2 activity in a time-dependent manner. Protein kinase C is involved in high glucose-induced iPLA2 βprotein up-regulation. Inhibiting iPLA2β activity with bromoenol lactone or preventing its expression by genetic deletion abolishes high glucose-induced RhoA/Rho kinase/CPI-17 activation, and restoring expression of iPLA2β in iPLA2β-deficient cells also restores high glucose-induced CPI-17 phosphorylation. Pharmacological and genetic inhibition of 12/15-lipoxygenases has effects on high glucose-induced CPI-17 phosphorylation similar to iPLA2β inhibition. Moreover, increases in iPLA2 activity and iPLA2β protein expression are also observed in both type 1 and type 2 diabetic vasculature. Pharmacological and genetic inhibition of iPLA2β, but not iPLA2γ, diminishes diabetes-associated vascular smooth muscle hypercontractility. In summary, our results reveal a novel mechanism by which high glucose-induced, protein kinase C-mediated iPLA2β up-regulation activates the RhoA/Rho kinase/CPI-17 via 12/15-lipoxygenases and thereby contributes to diabetes-associated vascular smooth muscle hypercontractility.

Original languageEnglish
Pages (from-to)8628-8638
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number12
DOIs
StatePublished - Mar 19 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Role of calcium-independent phospholipase a2β in high glucose-induced activation of RhoA, Rho Kinase, and CPI-17 in cultured vascular smooth muscle cells and vascular smooth muscle hypercontractility in diabetic animals'. Together they form a unique fingerprint.

Cite this