Abstract
Metabolic syndrome is associated with reduced endothelial vasodilator function. It is also associated with the induction of cyclooxygenase-2 (COX2), which produces vasoactive prostanoids. The frequency of metabolic syndrome increases with age and aging per se is a risk factor associated with reduced endothelium-mediated relaxation. Nevertheless, the combined effect of aging and metabolic syndrome on the endothelium is less known. We hypothesized that COX2 derived prostanoids may affect endothelium function in metabolic syndrome associated with aging. We used obese Zucker rats, a model of metabolic syndrome. First order mesenteric arteries were isolated from 4- and 12-month-old rats and acetylcholine (endothelium)-dependent relaxation determined using wire-myography. Endothelium-mediated relaxation, impaired in young Zucker rats (89 versus 77% maximal relaxation; lean versus Zucker), was further reduced in old Zucker rats (72 versus 51%, lean versus Zucker). The effect of the nitric oxide-synthesis inhibitor L-NAME on the relaxation was reduced in both young and old Zucker rats without change in eNOS expression level. COX inhibition (indomethacin) improved acetylcholine-mediated relaxation in old obese rats only, suggesting involvement of vasoconstrictor prostanoids. In addition, COX2 inhibition (NS398) and TxA2/PGH2 receptor blockade (SQ29548) both improved relaxation in old Zucker rat arteries. Old Zucker rats had the highest TxB2 (TxA2 metabolite) blood level associated with increased COX2 immunostaining. Chronic COX2 blockade (Celecoxib, 3 weeks) restored endothelium-dependent relaxation in old Zucker rats to the level observed in old lean rats. Thus the combination of aging and metabolic syndrome further impairs endothelium-dependent relaxation by inducing an excessive production of COX2-derived vasoconstrictor(s); possibly TxA2.
Highlights
Obesity is a fast growing problem worldwide (James, 2004) and is associated with an increasing risk of cardiovascular morbidity and mortality, especially when it is associated with other risk factors in the metabolic syndrome (Hu et al, 2004)
Acetylcholine-mediated relaxation was significantly reduced in obese Zucker rats compared to lean rats and the combination of metabolic syndrome and aging further impaired endothelium-dependent relaxation (Figures 1A,B)
The novel finding of the present study is that the combined effect of metabolic syndrome and aging in a rat model, the obese Zucker rat, further impaired endothelium-dependent dilation due to COX2dependent production of TxA2
Summary
Obesity is a fast growing problem worldwide (James, 2004) and is associated with an increasing risk of cardiovascular morbidity and mortality, especially when it is associated with other risk factors in the metabolic syndrome (Hu et al, 2004). Studies in human (Arkin et al, 2008) or in obese Zucker rats, a model of hyperphagia-induced metabolic syndrome, have reported endothelium dysfunction in several vascular beds (Zanchi et al, 1995) associated with a reduced NO bioavailability (Bohlen, 2004). Metabolic syndrome is associated with increased thromboxane A2 (TXA2)-mediated vasoconstriction and endothelium dysfunction (Xiang et al, 2006, 2008). These studies suggest that COX2 might be involved in this production of TXA2
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