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COX-2: a transitional endothelial response against the deleterious effects of reactive oxygen species in dyslipidemia
Reactive oxygen species (ROS) contribute to impair the endothelial function associated with the aging process and risk factors for cardiovascular diseases such as dyslipidemia (DL) ( Madamanchi et al., 2005). The impact of DL-associated ROS production on ageing-induced endothelial dysfunction has not been studied. The aims of this study were to evaluate the mechanisms involved in ROS-induced decrease in the dilatation of renal arteries isolated from aging DL mice. Renal arteries (n=6 mice per group) were isolated from young (3 m/o; 27±1g), mature (6 m/o; 38±1g), adult (12 m/o; 46±2g) and old (20 m/o; 52±7g) C57Bl/6 (WT) male mice as well as young (3 m/o; 32±1g), mature (6 m/o; 42±1g), adult (12 m/o; 51±2g) and old (20 m/o; 37±5g) DL male mice expressing the human apolipoprotein B-100, leading to an increase in 50% of total cholesterol and 100% triglycerides (Krummen et al., 2005). Vessels were pressurized at 100 mm Hg in an arteriograph (Vequaud & Thorin, 2001). Endothelium-dependent dilatations to acetylcholine (ACh, 1nM-30 µM) were obtained in vessels pre-contracted with phenylephrine (30 µM) in absence and presence of indomethacin (INDO, 10µM), a cyclooxygenase (COX) inhibitor, alone or combined with N-acetyl-L-cystein (NAC, 10µM), a ROS scavenger. The expression of COX-2 and iNOS and the levels of HNE, a marker of ROS-induced lipid peroxidation, were observed by immunfluorescence with confocal imaging. ACh-induced maximal dilatation was significantly decreased at 12 months (64±10% of max dilatation; mean±sem, P<0.05) in WT mice, but at 6 months (61±10%; P<0.05) in DL mice, compared to 3 months (91±5% and 93±4%, in WT and DL, respectively). INDO did not alter the dilatation induced by ACh in renal arteries isolated from WT mice, while INDO reduced (P<0.05) ACh-induced maximal dilatation (29±13% vs 64±12% without INDO) in 12 months old DL mice. NAC — combined to INDO — did not affect ACh-induced dilatation of arteries from WT mice but completely normalized (P<0.05) endothelial function at 6 months in DL mice (95±1%) and reversed (P<0.05) the inhibitory effect of INDO at 12 months (65±13%). At 20 months, the maximal dilatation was minimal in both groups (48±10% and 38±12% in WT and DL mice, respectively) and insensitive to INDO alone or combined with NAC. Confocal imaging revealed, in DL mice only, a parallel increase in COX-2, iNOS and HNE expression with aging, which was maximal at 12 months. In conclusion, this study suggests that DL-associated ROS production hastens the development of the endothelial dysfunction. Simultaneous increase of COX-2 expression and vascular sensitivity to INDO suggests the presence of a transitory compensatory mechanism fighting against the deleterious effects of ROS at 12 months.
Krummen et al. (2005). Br. J. Pharmacol., in press. |
