End-organs perfusion is altered in metabolic diseases due in part to a decreased endothelium-mediated relaxation in resistance arteries (RA). Infl ammatory factors including cyclooxygenase-2 (COX2) derived agents affect the endothelium to different degrees in aging and obesity but the effect of their association on the endothelium is not fully understood. We hypothesized that COX2 derivatives might reduce endothelium-mediated relaxation in aging associated with obesity. RA from 4 and 12 month-old obese Zucker rats RA were isolated to measure acetylcholine (endothelium)-mediated relaxation (AMR), in vitro, using wire-myography.
Impaired with obesity in young rats, AMR was further reduced with aging in old obese rats (89 versus 77 % maximal relaxation, young versus old lean rats and 72 versus 51 %, old young versus old obese rats). Endothelial NO-synthase (eNOS) blockade (L-NAME) was reduced in old obese rats although eNOS expression level was unaffected. However, indomethacin improved AMR in old obese rats only, suggesting that vasoconstrictor prostanoids were involved. Similarly, COX2 inhibition (NS398) and TxA2/PGH2 receptor blockade (SQ29548) increased AMR in arteries from old obese rats only. Old obese rats presented the highest levels of blood TxB2 (TxA2 metabolite) associated with an increased COX2 immunostaining and expression level. Chronic inhibition of COX2 with NS398 (3 weeks) restored AMR in old obese rats (78 % versus 57 % in control obese rats) to the level observed in solventtreated old lean rats (84 %). Taken together, these data show that obesity in old rats is associated with a reduced endothelium-mediated relaxation due to an excessive production of COX-2 derivatives, most probably TxA2.Le texte complet de cet article est disponible en PDF.