Inhibition of Tumor Necrosis Factor Reverses Vascular Aging

Cardiovascular researchers have found that some of the detrimental effects of aging on blood vessels can be alleviated by treatment with a drug that binds and inhibits the inflammatory protein tumor necrosis factor alpha (TNF-alpha).

Investigators at New York Medical College (Valhalla, USA) tested the effect of the known TNF-alpha inhibitor, etanercept, on the blood vessels of a group of aged laboratory rats. Etanercept is made from the combination of two naturally occurring soluble human 75-kilodalton TNF receptors linked to an Fc portion of an immunoglobulin gamma 1 (IgG1). The effect is an artificially engineered antibody.

The 29 month-old F344 rats were treated with one mg/kg etanercept per week for four weeks. Blood vessels were then removed and examined. Results published in the January 2007 issue of the American Journal of Pathology revealed that etanercept treatment significantly improved response to acetylcholine and decreased vascular NAD(P)H oxidase activity and expression. Etanercept treatment decreased DNA fragmentation rate and caspase 3/7 activity (indicating an increased rate of apoptotic cell death) as compared to the aged carotid and coronary arteries of untreated, control animals. Furthermore, the treatment decreased the up-regulation of inflammatory markers, including inducible nitric-oxide synthase and intercellular adhesion molecule-1.

The investigators also treated young animals with TNF-alpha. In this case they found that the protein caused changes in the young blood vessels that caused them to resemble the blood vessels of the aged animals. These effects included endothelial dysfunction, oxidative stress, and increased apoptosis and pro-inflammatory gene expression.

The authors concluded, "We propose that anti-TNF-alpha treatment exerts anti-aging vasculoprotective effects.”



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