title: Cell-specific and endothelium-dependent regulations of matrix metalloproteinase-2 in rat aorta.
abstract: Chronic activation of angiotensin II (ANGII) and matrix metalloproteinase-2 (MMP-2) during hypertension contributes to increased aortic stiffness. We studied signalling mechanisms employed by ANGII in the regulation of latent (pro-) and active forms of MMP-2 in rat aortic endothelial and smooth muscle cells, along with isolated rat aorta. Using western blotting, we demonstrate that ANGII (1 µmol/L) significantly (P < 0.01) increases pro-MMP-2 protein expression after 8 h not only in endothelial and smooth muscle cells, but also in isolated rat aorta. We demonstrate that ANGII acts via AT1 receptor-activated cell-specific pathways. In endothelial cells, the JNK1/c-jun pathway is activated, whereas in smooth muscle cells, the JAK2/STAT3 pathway. Activation of JAK2/STAT3 pathway in response to ANGII was EGF receptor-dependent. Results obtained in cell culture are in agreement with the results obtained in isolated aorta. However, active MMP-2 was not found under cell culture conditions, whereas in isolated aorta, active MMP-2 was significantly (P < 0.05) increased after stimulation with ANGII, as detected by gelatine zymography. This increase of MMP-2 activity was not inhibited by blocking the pathways we identified to control pro-MMP-2 protein expression, but was abolished in the absence of endothelium. Our findings demonstrate that ANGII regulates pro-MMP-2 protein expression via cell-specific pathways in rat aorta. The endothelium may play an essential role in the activation of pro-MMP-2. These results may lead to new strategies for inhibiting MMP-2 expression and activity in distinct cell types of the aortic wall.
authors.affiliation: Medical Faculty Carl Gustav Carus, Department of Physiology, TU Dresden, Fetscherstr. 74, Dresden, Germany.
authors.forename: Irakli
authors.initials: I
authors.lastname: Kopaliani
authors.forename: Melanie
authors.initials: M
authors.lastname: Martin
authors.forename: Birgit
authors.initials: B
authors.lastname: Zatschler
authors.forename: Katrin
authors.initials: K
authors.lastname: Bortlik
authors.forename: Bianca
authors.initials: B
authors.lastname: Müller
authors.forename: Andreas
authors.initials: A
authors.lastname: Deussen
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D004792:Enzyme Precursors; D016755:Proto-Oncogene Proteins c-jun; D044140:Receptor, Angiotensin, Type 1; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D000804:Angiotensin II; C483803:Egfr protein, rat; D066246:ErbB Receptors; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D048055:Mitogen-Activated Protein Kinase 8; D018093:Gelatinases; C069860:progelatinase; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat