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 prooxidative environment. Upregulation of this pathway compensates for the early loss of the contribution of NO in DL mice.