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Role of cyclooxygenae‐1 and ‐2 in endothelium‐dependent contraction of atherosclerotic mouse abdominal aortas

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Clinical and Experimental Pharmacology and Physiology

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Objective To determine the role of cyclooxygenase (COX)‐1 or ‐2 in endothelium‐dependent contraction under atherosclerotic conditions. Methods Atherosclerosis was induced in apoE knockout (apoE‐/‐) mice and those with COX‐1‐/‐ (apoE‐/‐‐COX‐1‐/‐) by feeding with high fat and cholesterol food. Aortas (abdominal or the whole section) were isolated for functional and/or biochemical analyses. Results As in non‐atherosclerotic conditions, the muscarinic receptor agonist acetylcholine (ACh) evoked an endothelium‐dependent, COX‐mediated contraction following NO synthase (NOS) inhibition in abdominal aortic rings from atherosclerotic apoE‐/‐ mice. Interestingly, COX‐1 inhibition not only abolished such a contraction in rings showing normal appearance, but also diminished that in rings with plaques. Accordingly, only a minor contraction (<30% that of apoE‐/‐ counterparts) was evoked by ACh (following NOS inhibition) in abdominal aortic rings of atherosclerotic apoE‐/‐‐COX‐1‐/‐ mice with plaques, and none was evoked in those showing normal appearance. Also, the contraction evoked by ACh in apoE‐/‐‐COX‐1‐/‐ abdominal aortic rings with plaques was abolished by non‐selective COX inhibition, thromboxane‐prostanoid (TP) receptor antagonism, or endothelial denudation. Moreover, we noted that ACh evoked a predominant production of the prostacyclin (PGI2, which mediates abdominal aortic contraction via TP receptors in mice) metabolite 6‐keto‐PGF1α, which was again sensitive to COX‐1 inhibition or COX‐1‐/‐. Conclusion In atherosclerotic mouse abdominal aortas, COX‐1 can still be the major isoform mediating endothelium‐dependent contraction, which probably results largely from PGI2 synthesis as in non‐atherosclerotic conditions. In contrast, COX‐2 may have only a minor role in such response limited to areas of plaques under the same pathological condition. This article is protected by copyright. All rights reserved.