Vascular endothelial dysfunction in aging: loss of Akt-dependent endothelial nitric oxide synthase phosphorylation and partial restoration by (R)-alpha-lipoic acid.

Aging is the single largest risk factor for cardiovascular diseases, which in turn are the leading cause of death of individuals over the age of 65 years. In part, this risk is due to a profound loss of vasomotor function of the major conduit arteries, primarily because of lower levels of endothelial-derived nitric oxide. The mechanisms involved in vascular dysfunction are not entirely understood, but age-related alterations in eNOS (endothelial nitric oxide synthase) activity appear to be a likely source of the aging lesion. However, age-related changes in cell signalling that ultimately affect eNOS phosphorylation and its activity have not been explored. Results in our laboratory indicate that levels of eNOS phosphorylation in aortas from aged F344xBN rats (28-30 months old) are almost 50% lower than in aortas from young animals (3 months old). Lower eNOS phosphorylation is directly attributable to loss of constitutive Akt/protein kinase B activity. The decline in eNOS phosphorylation can be partially restored by treating old rats with (R)-alpha-lipoic acid. These results thus suggest that age-related changes in eNOS phosphorylation may be a significant factor in the overall loss of vasomotor function in the elderly.