Unknown

Dataset Information

0

Role of calcium-independent phospholipase A2beta 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.


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 A(2)beta (iPLA(2)beta) 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(2)beta mRNA, protein, and iPLA(2) activity in a time-dependent manner. Protein kinase C is involved in high glucose-induced iPLA(2)beta protein up-regulation. Inhibiting iPLA(2)beta 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 iPLA(2)beta in iPLA(2)beta-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 iPLA(2)beta inhibition. Moreover, increases in iPLA(2) activity and iPLA(2)beta protein expression are also observed in both type 1 and type 2 diabetic vasculature. Pharmacological and genetic inhibition of iPLA(2)beta, but not iPLA(2)gamma, diminishes diabetes-associated vascular smooth muscle hypercontractility. In summary, our results reveal a novel mechanism by which high glucose-induced, protein kinase C-mediated iPLA(2)beta up-regulation activates the RhoA/Rho kinase/CPI-17 via 12/15-lipoxygenases and thereby contributes to diabetes-associated vascular smooth muscle hypercontractility.

SUBMITTER: Xie Z 

PROVIDER: S-EPMC2838285 | BioStudies | 2010-01-01

REPOSITORIES: biostudies

Similar Datasets

2007-01-01 | S-EPMC4123227 | BioStudies
2003-01-01 | S-EPMC1223565 | BioStudies
2005-01-01 | S-EPMC1180727 | BioStudies
2016-01-01 | S-EPMC4751395 | BioStudies
2012-01-01 | S-EPMC3330734 | BioStudies
2016-01-01 | S-EPMC4991059 | BioStudies
2018-01-01 | S-EPMC5746525 | BioStudies
2006-01-01 | S-EPMC1450000 | BioStudies
1000-01-01 | S-EPMC2212616 | BioStudies
2002-01-01 | S-EPMC1222907 | BioStudies