on July 17, 2008
Published online before print July 17, 2008, doi: 10.1161/ATVBAHA.108.168955
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Submitted on April 21, 2008
Accepted on June 27, 2008
Platelet-Derived RANTES Mediates Hypercholesterolemia-Induced Superoxide Production and Endothelial Dysfunction
Ryan M. Wolfort ;
From the Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport.
* To whom correspondence should be addressed. E-mail: dgrang{at}lsuhsc.edu.
Background—Hypercholesterolemia (HC) is known to elicit oxidative stress and impair endothelium-dependent vasodilation (EDV) in arterioles and large arteries. Although RANTES, a chemokine that promotes the recruitment of leukocytes, has been implicated in atherosclerosis, its role in HC has not been previously evaluated.
Methods and Results—Wire myography, a cytochrome C reduction assay, and RT-PCR were used to assess the HC-induced responses of aortic rings from wild-type (WT), RANTES-deficient (RANTES-/-), bone marrow chimeras (WT
WT, RANTES-/-WT, and WTRANTES-/-), and WT mice receiving antiplatelet serum (APS) to induce thrombocytopenia. HC led to superoxide (O2-) production, Nox-2 expression, and EDV dysfunction in WT mice with a corresponding increase in plasma RANTES concentration. The HC-induced responses were absent in RANTES-/-, RANTES-/-WT chimeras, and APS-treated WT mice. Exposure of WT aortic rings to RANTES elicited EDV impairment and O2- production, which were blocked by incubation with heparin or metRANTES. Aortic rings from CD44-deficient mice exhibited responses similar to WT after RANTES incubation, suggesting that CD44 does not act as an auxiliary receptor in RANTES-mediated responses with HC.
Conclusions—These findings are consistent with a mechanism whereby HC promotes platelet release of RANTES, inducing a glycosaminoglycan- and CCR-dependent enhancement of O2- production with impairment of EDV.