Cardiovascular Research Advance Access first published online on March 15, 2009
This version [Corrected Proof] published online on April 2, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp089
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Impaired vascular function in small resistance arteries of LOX-1 overexpressing mice on high-fat diet
1 Department of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, University of Technology, Fetscherstr. 74, D-01307 Dresden, Germany
2 Department of Vascular Endothelium and Microcirculation, Medical Faculty Carl Gustav Carus, University of Technology, Dresden, Germany
3 Department of Vascular Physiology, National Cardiovascular Center Research Institute, Suita, Osaka, Japan
* Corresponding author. Tel: +49 351 458 6261; fax: +49 351 458 6315. E-mail address: birgit.eichhorn{at}tu-dresden.de
Aims: LOX-1 is a major vascular receptor for oxidized low-density lipoprotein (oxLDL). In this study, we analysed the impact of LOX-1 overexpression and high dietary fat intake on vascular function in small resistance arteries.
Methods and results: Relaxation of mesenteric arteries was measured using a wire myograph. Compared with the control group, mice overexpressing LOX-1 on a high-fat diet (FD) had preserved vascular smooth muscle relaxation, but impaired endothelium-dependent relaxation via NO. Vascular NO availability was decreased by exaggerated formation of reactive oxygen species and decreased endothelial NO synthase expression. Endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation via cytochrome P450 metabolites was increased in LOX-1 + FD animals, but did not completely compensate for the loss of NO. Currents of calcium-activated potassium channels with large conductance (BKCa channels) were measured by the voltage-clamp method. The BKCa current amplitudes were not altered in endothelial cells, but highly increased in vascular smooth muscle cells from resistance arteries of LOX-1-overexpressing mice on FD. BKCa currents were activated by low-dose H2O2 and cytochrome P450 metabolites 11,12-EET and 14,15-EET as EDHF in control mice.
Conclusion: LOX-1 overexpression and FD caused functional changes in endothelial and vascular smooth muscle cells of small resistance arteries.
KEYWORDS Endothelial function; K+-channel; Lipoproteins; Smooth muscle; Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)
Time for primary review: 28 days