Angiotensin-converting enzyme regulates bradykinin receptor gene expression.
The angiotensin-converting enzyme (ACE) is a membrane-bound peptidyl dipeptidase known to act on a variety of peptide substrates in the extracellular space. Its most notable functions are the formation of angiotensin II and the degradation of bradykinin. In the current experiments, we found that exogenous ACE added to vascular smooth muscle cell culture strongly induces and upregulates the genes of bradykinin receptors B1 and B2. This transcriptional regulatory property of ACE was shown to be unrelated to its known enzymatic properties. Indeed, ACE at 3.75 microg/ml added in the culture medium of vascular smooth muscle cells was found to cause marked upregulation of the mRNA expression of the genes for the B1 and B2 receptors of bradykinin by 22- and 11-fold, respectively. This phenomenon was not altered by the addition of specific angiotensin II antagonists for the AT1 or AT2 receptors. Moreover, the ACE inhibitor captopril, which inhibited ACE enzymatic activity, did not block its effect at the bradykinin receptor gene transcription level. Expression of both receptor genes was completely abolished by actinomycin D. Furthermore, transcriptional upregulation was inhibited by curcumin, suggesting involvement of different transcriptional factors in this phenomenon. Electrophoretic mobility shift assay revealed increase in NF-kappaB and activator protein-1 protein binding for consensus sequences, between ACE-treated cells versus untreated cells. The data indicate a novel biological function of the ACE unrelated to its well-known enzymatic function as a peptidyl dipeptidase.
Ignjacev-Lazich
Ivana
I
Hypertension & Atherosclerosis Section, Boston Univ. School of Medicine, 715 Albany St., Boston, MA, USA.
Kintsurashvili
Ekaterina
E
Johns
Conrado
C
Vitseva
Olga
O
Duka
Arvi
A
Shenouda
Sherene
S
Gavras
Irene
I
Gavras
Haralambos
H
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000737:chemistry; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1 / Q000096:biosynthesis / Q000235:genetics; D043782:Receptor, Bradykinin B2 / Q000096:biosynthesis / Q000235:genetics; D018002:Receptors, Bradykinin / Q000096:biosynthesis* / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation
D047228:Angiotensin II Type 1 Receptor Blockers; D016328:NF-kappa B; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D018808:Transcription Factor AP-1; D012313:RNA; D000242:Cyclic AMP; D007703:Peptidyl-Dipeptidase A