Low-dose aspirin prevents age-related endothelial dysfunction in a mouse model of physiological aging

Abstract

The age-related impairment of endothelium-dependent vasodilatation contributes to increased cardiovascular risk in the elderly. For primary and secondary prevention, aspirin can reduce the incidence of cardiovascular events in this patient population. The present work evaluated the effect of low-dose aspirin on age-related endothelial dysfunction in C57B/J6 aging mice and investigated its protective antioxidative effect. Agerelated endothelial dysfunction was assessed by the response to acetylcholine of phenylephrine-induced precontracted aortic segments isolated from 12-, 36-, 60-, and 84-wk-old mice. The effect of low-dose aspirin was examined in mice presenting a decrease in endothelial-dependent relaxation (EDR). The effects of age and aspirin treatment on structural changes were determined in mouse aortic sections. The effect of aspirin on the oxidative stress markers malondialdehyde and 8-hydroxy-2Ј-deoxyguanosine (8-OhdG) was also quantified. Compared with that of 12-wk-old mice, the EDR was significantly reduced in 60-and 84-wk-old mice (P Ͻ 0.05); 68-wkold mice treated with aspirin displayed a higher EDR compared with control mice of the same age (83.9 Ϯ 4 vs. 66.3 Ϯ 5%; P Ͻ 0.05). Aspirin treatment decreased 8-OHdG levels (P Ͻ 0.05), but no significant effect on intima/media thickness ratio was observed. The protective effect of aspirin was not observed when treatment was initiated in older mice (96 wk of age). It was found that low-dose aspirin is able to prevent age-related endothelial dysfunction in aging mice. However, the absence of this effect in the older age groups demonstrates that treatment should be initiated early on. The underlying mechanism may involve the protective effect of aspirin against oxidative stress. endothelium; intima/media; vasodilatation; oxidative stress AGE-ASSOCIATED CHANGES SUCH as endothelial dysfunction are involved in the significantly increased risk of cardiovascular complications and microthrombus formation in the elderly patient population (44). The presence of endothelial dysfunction in the coronary or peripheral circulation has been shown to constitute a risk factor for cardiovascular events independent of the development of atherosclerosis or other vascular risk factors (22,(43)(44)(45). There is emerging evidence that age-associated endothelial dysfunction is related to the local formation of reactive oxygen and nitrogen species within and in the vicinity of the vascular wall (13,25,36,43,49). Therapeutic approaches capable of preventing or reversing age-related endothelial dysfunction may thus help to reduce cardiovascular risk in the elderly.Age-related endothelial-dependent relaxation (EDR) decreases in the large vessels of different animal species including humans (36). EDR in response to acetylcholine (ACh) decreases with age in the rat aorta: the maximal relaxation effect of ACh is 100% in 4-to 6-wk-old, 50% in 3-to 6-mo-old, and 25% in 12-to 25-mo-old rats (29). The agerelated decrease in EDR varies from one vessel to another and from one species to anot...

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“…Although atherosclerosis does not spontaneously develop in C57BL/6J mice, histopathological changes reminiscent of arterial precursor lesions (e.g., accumulation of glycosaminoglycans and chronic inflammatory infiltrates) do occur in mice (25). Additionally, during aging, arteries lose their elasticity due to elastic fiber fragmentation and excessive collagen deposition in the arterial wall (25). We performed histopathological analyses of aortic sections, assessing the arterial wall for the presence of degenerative changes (i.e., division and disorganization of elastic fibers and replacement of smooth muscle cells by mucinous substance).…”

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