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An angiotensin II- and NF-kappaB-dependent mechanism increases connexin 43 in murine arteries targeted by renin-dependent hypertension.
AIMS: Connexins (Cxs) play a role in the contractility of the aorta wall. We investigated how connexins of the endothelial cells (ECs; Cx37, Cx40) and smooth muscle cells (SMCs; Cx43, Cx45) of the aorta change during renin-dependent and -independent hypertension. METHODS AND RESULTS: We subjected both wild-type (WT) mice and mice lacking Cx40 (Cx40(-/-)), to either a two-kidney, one-clip procedure or to N-nitro-l-arginine-methyl-ester treatment, which induce renin-dependent and -independent hypertension, respectively. All hypertensive mice featured a thickened aortic wall, increased levels of Cx37 and Cx45 in SMC, and of Cx40 in EC (except in Cx40(-/-) mice). Cx43 was up-regulated, with no effect on its S368 phosphorylation, only in the SMCs of renin-dependent models of hypertension. Blockade of the renin-angiotensin system of Cx40(-/-) mice normalized blood pressure and prevented both aortic thickening and Cx alterations. Ex vivo exposure of WT aortas, carotids, and mesenteric arteries to physiologically relevant levels of angiotensin II (AngII) increased the levels of Cx43, but not of other Cx. In the aortic SMC line of A7r5 cells, AngII activated kinase-dependent pathways and induced binding of the nuclear factor-kappa B (NF-kappaB) to the Cx43 gene promoter, increasing Cx43 expression. CONCLUSION: In both large and small arteries, hypertension differently regulates Cx expression in SMC and EC layers. Cx43 is selectively increased in renin-dependent hypertension via an AngII activation of the extracellular signal-regulated kinase and NF-kappaB pathways.
Angiotensin II/metabolism, Angiotensin II Type 1 Receptor Blockers/pharmacology, Angiotensin-Converting Enzyme Inhibitors/pharmacology, Animals, Antihypertensive Agents/pharmacology, Aorta/drug effects, Aorta/metabolism, Binding Sites, Blood Pressure, Carotid Arteries/metabolism, Carotid Arteries/physiopathology, Cell Line, Connexin 43/genetics, Connexin 43/metabolism, Connexins/deficiency, Connexins/genetics, Disease Models, Animal, Endothelial Cells/metabolism, Extracellular Signal-Regulated MAP Kinases/metabolism, Genes, Reporter, Hypertension, Renovascular/drug therapy, Hypertension, Renovascular/etiology, Mesenteric Arteries/metabolism, Mesenteric Arteries/physiopathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocytes, Smooth Muscle/metabolism, NF-kappa B/metabolism, NG-Nitroarginine Methyl Ester, Nephrectomy, Phosphorylation, Promoter Regions, Genetic, Rats, Renin/blood, Time Factors, Transfection, Up-Regulation
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