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- Title
Endothelin-Mediated Vasoconstriction in Early Atherosclerosis Is Markedly Increased in ApoE −/− Mouse but Prevented by Atorvastatin.
- Authors
Maguire, Janet J.; Wiley, Katherine E.; Kuc, Rhoda E.; Stoneman, Victoria E. A.; Bennett, Martin R.; Davenport, Anthony P.
- Abstract
We have discovered that endothelin-1 (ET-1) vasoconstriction is significantly enhanced in aortas of young (8–16-week-old) apolipoprotein E–deficient (ApoE−/−) mice devoid of atherosclerotic lesions (maximum response expressed as a percentage of the mean response to 100 m M KCl (EMAX) = 55.7% ± 19.5% KCl, n = 5) compared to age-matched C57BL/6/J control animals (EMAX = 12.6% ± 2.5% KCl, n = 8), indicating that alterations in the endothelin system may contribute to disease progression, at least in this animal model. There was no difference in the potency of ET-1 to contract aorta from the two groups (C57BL/6/J pD2 = 8.74 ± 0.30; ApoE−/− pD2 = 8.50 ± 0.15, P > 0.05). This increased response was specific to ET-1, as it was not observed with phenylephrine or U46619, nor was it due to a non–receptor mediated increase in contractile sensitivity, as there was no change in response to KCl between the two groups. [125I]ET-1 bound with subnanomolar affinity (KD) to aorta (KD == 0.018 ± 0.002 n M, n == 4) and, with an order of magnitude lower affinity, to heart (KD == 0.47 ± 0.05, n == 5) of C57BL/6/J mice with binding densities (BMAX) of 9.3 ± 2.4 fmol mg−1protein and 100 ± 14 fmol mg−1 protein, respectively. Alterations in vascular reactivity to ET-1 could not be explained by increased endothelin receptor density or affinity, as these were not altered in aorta (KD == 0.011 ± 0.003 n M ; BMAX == 10.1 ± 3.9 fmol mg−1, n == 4) and heart (KD == 0.43 ± 0.04 n M ; BMAX == 115 ± 26 fmol mg−1, n == 6) of ApoE−/− animals. The ratio of ETA to ETB receptors in heart of control and ApoE−/− mice was similar, comprising 89% and 85% ETA receptors, respectively. In isolated aorta from ApoE−/− mice on the Western diet, which more closely resembled more advanced stages of the disease in man, the augmented ET-1 vasoconstrictor response was maintained (EMAX == 25.2% ± 6.8% KCl, n == 9); however, it was completely prevented in animals that had received 10 weeks of oral atorvastatin (30 mg kg−1 day−1) (EMAX == 4.0% ± 1.5% KCl, n == 5), a concentration that was chosen because it did not affect plasma cholesterol and triglyceride levels. Therefore, this protective prevention of enhanced ET-1 vasoconstriction in ApoE−/− mice by atorvastatin was independent of its lipid-lowering properties.
- Publication
Experimental Biology & Medicine, 2006, Vol 231, Issue 6, p806
- ISSN
1535-3702
- Publication type
Article
- DOI
10.3181/00379727-231-2310806