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Effect of low density lipoprotein on Rho‐dependent proliferation in vascular smooth muscle cells
Author(s) -
O’Shaughnessy Deirdre,
Miller Yury,
Brown Joan Heller,
Seasholtz Tammy
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a666
Subject(s) - rhoa , vascular smooth muscle , chemistry , dna synthesis , thrombin , microbiology and biotechnology , apoptosis , smooth muscle , cell growth , dna , biochemistry , signal transduction , endocrinology , medicine , biology , platelet
Our previous studies have shown that G protein coupled receptor (GPCR) agonists signaling through Gα 12/13 , such as thrombin, activate RhoA and produce Rho‐dependent DNA synthesis in vascular smooth muscle cells. Mounting evidence from our lab and others suggests that Rho signaling is deregulated in a variety of vascular diseases. Minimally oxidized LDL (mmLDL) is an early product of progressive LDL oxidation in atherosclerotic lesions, and extensively oxidized LDL (oxLDL) is for the most part associated with advanced lesions. We examined the ability of three forms of LDL, native LDL (nLDL), mmLDL and oxLDL to activate RhoA. Rho‐dependent changes in rat aortic smooth muscle cell (RASMC) proliferation were examined and compared to those we have observed in response to thrombin. The current studies demonstrate that nLDL and mmLDL lead to acute activation of RhoA (3.5 minutes and 1 hour, respectively), whereas oxLDL had no effect on RhoA activation up to 6 hours. In addition, treatment of RASMC with nLDL or mmLDL but not oxLDL resulted in an increase in DNA synthesis. Inhibition of RhoA with C3 exoenzyme blocked nLDL and mmLDL induced proliferation, suggesting that the effects of these agents are RhoA‐dependent. Surprisingly, oxLDL inhibited basal and thrombin‐stimulated DNA synthesis. In addition we observed that inhibition of ROCK with Y‐27632 greatly enhanced the ability of oxLDL to inhibit basal DNA synthesis. Current studies are aimed at determining the mechanism(s) by which oxLDL inhibits DNA synthesis and examining its ability to induce apoptosis in these cells.