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Am J Physiol Cell Physiol ; 315(3): C367-C379, 2018 09 01.
Article in English | MEDLINE | ID: mdl-29874111

ABSTRACT

Hypertension is a global health problem, and angiotensin I (ANG I)-converting enzyme (ACE) inhibitors are largely used to control this pathology. Recently, it has been shown that ACE can also act as a transducer signal molecule when its inhibitors or substrates bind to it. This new role of ACE could contribute to understanding some of the effects not explained by its catalytic activity only. In this study, we investigated signaling pathway activation in Chinese hamster ovary (CHO) cells stably expressing ACE (CHO-ACE) under different conditions. We also investigated gene modulation after 4 h and 24 h of captopril treatment. Our results demonstrated that CHO-ACE cells when stimulated with ANG I, ramipril, or captopril led to JNK and ERK1/2 phosphorylation. To verify any physiological role at the endogenous level, we made use of primary cultures of mesangial cells from spontaneously hypertensive rats (SHR) and Wistar rats. Our results showed that ERK1/2 activation occurred mainly in primary cultures of mesangial cells from SHR rats upon captopril stimulation, suggesting that this signaling pathway could be differentially regulated during hypertension. Our results also showed that captopril treatment leads to a decrease of cyclooxygenase 2, interleukin-1ß, and ß-arrestin2 and a significant increase of AP2 gene expression levels. Our findings strengthen the fact that, in addition to the blockage of enzymatic activity, ACE inhibitors also trigger signaling pathway activation, and this may contribute to their beneficial effects in the treatment of hypertension and other pathologies.


Subject(s)
Angiotensin I/metabolism , Captopril/pharmacology , Peptidyl-Dipeptidase A/metabolism , Signal Transduction/drug effects , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , CHO Cells , Cell Line , Cricetulus , Hypertension/drug therapy , Hypertension/metabolism , MAP Kinase Signaling System/drug effects , Male , Mesangial Cells/drug effects , Mesangial Cells/metabolism , Phosphorylation/drug effects , Rats , Rats, Inbred SHR , Rats, Wistar
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