The binding of angiotensin converting enzyme (ACE) inhibitors to ACE has been suggested to elicit a cross-talk with the B2 kinin receptor in endothelial cells, implying that ACE might function as a signal transduction molecule. We have previously shown that ACE associates with CK2 and is phosphorylated on Ser1270 within its cytoplasmic tail. In the present study we determined whether ACE inhibitors affect the phosphorylation of ACE and/or the association of signal transduction molecules with the cytoplasmic tail. Incubation of endothelial cells with the ACE inhibitors ramiprilat and perindoprilat, or the ACE substrate bradykinin elicited ACE dimerisation and time-dependently enhanced the activity of ACE-associated CK2 as well as the phosphorylation of ACE at Ser1270. Angiotensin I failed to influence either ACE-associated CK2 activity or ACE phosphorylation. The c-Jun N-terminal kinase (JNK) associated with the cytoplasmic tail of ACE and treatment of endothelial cells with ramiprilat rapidly enhanced ACE-associated as well as total cellular JNK activity in vitro and in vivo (mouse lung). The ACE inhibitor also stimulated the accumulation of phosphorylated c-Jun in the nucleus. Neither the activation of JNK nor the phosphorylation and translocation of c-Jun were observed in endothelial cells over-expressing the non-phosphorylatable S1270A ACE mutant. Prolonged treatment with ramiprilat elicited an increase in ACE expression in vitro (cultured endothelial cells) and in vivo (mouse), an effect sensitive to the JNK inhibitor, SP 600125. Additionally, also the expression of COX2, another c-Jun-regulated protein gene, increased after ACE-inhibitor treatment. These results indicate that ACE is involved in outside-in signalling in endothelial cells and that the binding of an ACE inhibitor to ACE activates a signal transduction cascade that may account for the beneficial effects of ACE inhibitors in the cardiovascular system which cannot be attributed to the inhibition of angiotensin II formation or the prevention of bradykinin breakdown.</P>
Cardiovascular Pathology – Elsevier
Published: May 1, 2004
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