Aging associated with mild dyslipidemia reveals that COX-2 preserves dilation despite endothelial dysfunction.
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.
Gendron
Marie-Eve
ME
Institut de Cardiologie de Montréal, Centre de Recherche, 5000 rue Bélanger, Montréal, Québec, H1T 1C8, Canada.
Thorin-Trescases
Nathalie
N
Villeneuve
Louis
L
Thorin
Eric
E
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
D051546:Cyclooxygenase 2