title: Angiotensin II-induced MMP-2 activity and MMP-14 and basigin protein expression are mediated via the angiotensin II receptor type 1-mitogen-activated protein kinase 1 pathway in retinal pigment epithelium: implications for age-related macular degeneration.
abstract: Accumulation of various lipid-rich extracellular matrix (ECM) deposits under the retinal pigment epithelium (RPE) has been observed in eyes with age-related macular degeneration (AMD). RPE-derived matrix metalloproteinase (MMP)-2, MMP-14, and basigin (BSG) are major enzymes involved in the maintenance of ECM turnover. Hypertension (HTN) is a systemic risk factor for AMD. It has previously been reported that angiotensin II (Ang II), one of the most important hormones associated with HTN, increases MMP-2 activity and its key regulator, MMP-14, in RPE, inducing breakdown of the RPE basement membrane, which may lead to progression of sub-RPE deposits. Ang II exerts most of its actions by activating the mitogen-activated protein kinase (MAPK) signaling pathway. Herein is explored the MAPK signaling pathway as a potential key intracellular modulator of Ang II-induced increase in MMP-2 activity and MMP-14 and BSG protein expression. It was observed that Ang II stimulates phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK in RPE cells and ERK/p38 and Jun N-terminal kinase (JNK) in mice. These effects were mediated by Ang II type 1 receptors. Blockade of ERK or p38 MAPK abrogated the increase in MMP-2 activity and MMP-14 and BSG proteins in ARPE-19 cells. A better understanding of the molecular events by which Ang II induces ECM dysregulation is of critical importance to further define its contribution to the progression of sub-RPE deposits in AMD patients with HTN.
authors.affiliation: Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA.
authors.forename: Marianne
authors.initials: M
authors.lastname: Pons
authors.forename: Scott W
authors.initials: SW
authors.lastname: Cousins
authors.forename: Oscar
authors.initials: O
authors.lastname: Alcazar
authors.forename: Gary E
authors.initials: GE
authors.lastname: Striker
authors.forename: Maria E
authors.initials: ME
authors.lastname: Marin-Castaño
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D051926:Basigin / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006973:Hypertension / Q000150:complications / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008268:Macular Degeneration / Q000097:blood / Q000150:complications / Q000201:enzymology / Q000473:pathology; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012083:Renin / Q000097:blood; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D013599:Systole / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D051926:Basigin; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; D012083:Renin; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14