O35	ACE inhibitors stimulate endothelial COX-2 expression by a JNK-dependent ACE-signalling pathway.
K.Kohlstedt, R.Busse, I.Fleming
Institut für kardiovaskuläre Physiologie, JWG-Uniklinik, Frankfurt/Main, DE.

ACE inhibitors elicit an outside-in signalling via ACE in endothelial cells which initially involves the cytoplasmic phosphorylation of ACE on Ser1270 by the kinase CK2. The subsequent activation of the ACE-associated c-Jun N-terminal kinase (JNK) and the nuclear translocation of phosphorylated and thereby activated c-Jun affect endothelial gene expression. Since cyclooxygenase-2 (COX-2) is described as JNK/c-Jun-regulated protein and its expression is reported to be increased in subjects treated with ACE inhibitors, we determined whether ACE inhibitor-induced ACE-signalling causes upregulation in COX-2 expression. COX-2 expression was increased in lungs from mice treated with ramipril for 5 days and a similar increase in COX-2 protein was detected in primary cultures of human endothelial cells treated with ramiprilat. Furthermore, ramiprilat increased COX-2 promoter activity in an endothelial cell line stably expressing human somatic ACE, an effect not observed in either ACE-deficient cells or cells expressing a non-phosphorylatable ACE mutant (S1270A). The ramiprilat-induced and ACE-dependent increase in COX-2 expression and promoter activity was attenuated by pharmacological inhibition of JNK (SP600125) or by overexpression of dominant negative JNK. In ACE-expressing cells, ramiprilat significantly enhanced the DNA binding activity of AP-1 but did not affect that of CREB. The ACE inhibitor-induced increase in COX-2 protein and COX-2 promoter activity was attenuated by AP-1 decoy oligonucleotides. Ramiprilat did not affect AP-1 activity in ACE-deficient or in S1270A-expressing cells. As a consequence of the ramiprilat-induced increase in COX-2 expression, prostacyclin and to a much lesser extent prostaglandin E2, but not thromboxane A2, production was increased and was inhibited by the COX-2 inhibitor celecoxib. The increase in endothelial COX-2 expression and the subsequent increase in prostacyclin production via ACE inhibitor-induced ACE-signalling may account for some of the beneficial effects of ACE inhibitors on cardiovascular homeostasis.

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