title: Aging associated with mild dyslipidemia reveals that COX-2 preserves dilation despite endothelial dysfunction.
abstract: The endothelial function declines with age, and dyslipidemia (DL) has been shown to hasten this process by favoring the generation of reactive oxygen species (ROS). Cyclooxygenase-2 (COX-2) can be induced by ROS, but its contribution to the regulation of the endothelial function is unknown. Since COX-2 inhibitors may be deleterious to the cardiovascular system, we hypothesized that DL leads to ROS-dependent endothelial damage and a protective upregulation of COX-2. Dilations to acetylcholine (ACh) of renal arteries isolated from 3-, 6-, and 12-mo-old wild-type (WT) and DL mice expressing the human ApoB-100 were recorded with or without COX inhibitors and the antioxidant N-acetyl-l-cystein (NAC). Nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) were inhibited using N(omega)-nitro-l-arginine (l-NNA) and a depolarizing solution, respectively. In WT mice, the dilation to ACh declined at 12 mo but was insensitive to COX-1/2 inhibition alone or with NAC. DL led to an early endothelial dysfunction at 6 mo, normalized, however, by NAC. At 12 mo, vascular sensitivity to ACh was further reduced by DL. At this age, selective COX-2 inhibition reduced the dilation, whereas addition of NAC improved it. In 3- and 6-mo-old WT mice, l-NNA significantly reduced the dilation, whereas it limited the dilation only in 3-mo-old DL mice. EDHF-dependent dilation remains identical in both groups. These data suggest that COX-2 activity confers endothelium-dependent vasodilatory function in aged DL mice in the face of a pro-oxidative environment. Upregulation of this pathway compensates for the early loss of the contribution of NO in DL mice.
authors.affiliation: Institut de Cardiologie de Montréal, Centre de Recherche, 5000 rue Bélanger, Montréal, Québec, H1T 1C8, Canada.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Gendron
authors.forename: Nathalie
authors.initials: N
authors.lastname: Thorin-Trescases
authors.forename: Louis
authors.initials: L
authors.lastname: Villeneuve
authors.forename: Eric
authors.initials: E
authors.lastname: Thorin
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D050171:Dyslipidemias / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012077:Renal Artery / Q000503:physiopathology*; D014661:Vasoconstriction
chemical_list: D051546:Cyclooxygenase 2