Signaling via the Angiotensin-Converting Enzyme Enhances the Expression of Cyclooxygenase-2 in Endothelial Cells

Abstract

Abstract-Angiotensin-converting enzyme (ACE) inhibitors elicit outside-in signaling via ACE in endothelial cells. This involves the CK2-mediated phosphorylation of ACE on Ser 1270 and the activation of the c-Jun N-terminal kinase (JNK)/c-Jun pathway, resulting in an enhanced endothelial ACE expression. Because cyclooxygenase-2 (COX-2) expression is reported to be increased in subjects treated with ACE inhibitors, we determined the role of ACE signaling in this phenomenon and the transcription factors involved. In lungs from mice treated with the ACE inhibitor ramipril for 5 days, COX-2 expression was increased. A similar (1.5-to 2-fold) increase in COX-2 protein was detected in primary cultures of human endothelial cells treated with ramiprilat. In an endothelial cell line stably expressing human somatic ACE, ramiprilat increased COX-2 promoter activity, an effect not observed in ACE-deficient cells or cells expressing a nonphosphorylatable ACE mutant (S1270A). The ramiprilat-induced, ACE-dependent increase in COX-2 expression and promoter activity (both 1.5-to 2-fold greater than control) was prevented by the inhibition of JNK. Ramiprilat significantly enhanced the DNA binding activity of activator protein-1 in cells expressing ACE but not S1270A ACE. Activator protein-1 decoy oligonucleotides prevented the ACE inhibitor-induced increase in COX-2 promoter activity and protein expression. As a consequence of the ramiprilat-induced increase in COX-2 expression, prostacyclin and prostaglandin E 2 , but not thromboxane A 2 , production was increased and was inhibited by the COX-2 inhibitor celecoxib. These results indicate that ACE signaling may underlie the increase in COX-2 and prostacyclin levels in patients treated with ACE inhibitors. Key Words: angiotensin-converting enzyme Ⅲ cyclooxygenase Ⅲ endothelium Ⅲ prostacyclin Ⅲ ramipril Ⅲ signal transduction I nhibitors of the angiotensin-converting enzyme (ACE), such as ramipril, exert beneficial effects on endothelial function and vascular remodeling 1,2 and protect against the progression of atherosclerosis and the occurrence of cardiovascular events in humans. 3 Although the latter effects are generally attributed to a decrease in the ACE-mediated generation of angiotensin II and the accumulation of bradykinin, a number of the effects of ACE inhibitors cannot be accounted for by inhibition of the enzyme per se. 4 -6 One consequence of prolonged ACE inhibitor therapy is an increase in the expression of the enzyme itself. Increased ACE levels have been demonstrated in lung tissue and plasma from ACE inhibitor-treated rats 7,8 and in the serum from patients who distinctly benefit from ACE inhibitor therapy. 9,10 The finding that ACE inhibitors enhance the phosphorylation of ACE on Ser 1270 within the short cytoplasmic tail of the enzyme and thus induce the phosphorylation and nuclear translocation of c-Jun, 11 together with the report that the increase in ACE expression detected in phorbol esterstimulated endothelial cells can be attributed to the activity of an...

Amyloid β-Protein Is Degraded by Cellular Angiotensin-converting Enzyme (ACE) and Elevated by an ACE Inhibitor

“…Further, post-mortem analysis of AD brain tissue has shown significant elevation of ACE protein compared with control (28), perhaps representing an up-regulation of an A␤ clearance mechanism. Interestingly, initiation of ACE-mediated signal transduction by its substrates has been shown to up-regulate the enzyme's own expression via the c-Jun N-terminal kinase pathway (18,42). This feedback system provides a hypothetical mechanism by which ACE could modulate its own expression depending on levels of the A␤ substrate, leading to elevated levels of ACE in AD cortex.…”

Dihydroartemisinin transiently activates the JNK/SAPK signaling pathway in endothelial cells

“…In endothelial cells, the JNK signaling pathway specifically mediates the expression of cyclooxygenase-2 (Cox-2) and matrix metalloproteinase-13 (MMP-13) in response to a variety of cytokines (34,35). As revealed by RT-PCR, Cox-2 and MMP-13 transcription was significantly increased in HUVECs following treatment with 20 µM DHA for 24 h (P=0.010 and P=0.020, respectively; Fig.…”

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

“…158 ACEis also induce phosphorylation of the ACE intracellular tail (Ser 1270 ) via CK2, resulting in outside-in signaling that enhances expression of ACE and cyclooxygenase-2. 159 The effect of the ACE inhibitor on cyclooxygenase-2 is due to the transcription factor activator protein-1. This results in increased release of prostacyclin and prostaglandin E 2 by endothelial cells, which is independent of local accumulation of kinins.…”