title: Differential roles of endothelin-1 in angiotensin II-induced atherosclerosis and aortic aneurysms in apolipoprotein E-null mice.
abstract: Because both endothelin-1 (ET-1) and angiotensin II (AngII) are independent mediators of arterial remodeling, we sought to determine the role of ET receptor inhibition in AngII-accelerated atherosclerosis and aortic aneurysm formation. We administered saline or AngII and/or bosentan, an endothelin receptor antagonist (ERA) for 7, 14, or 28 days to 6-week- and 6-month-old apolipoprotein E-knockout mice. AngII treatment increased aortic atherosclerosis, which was reduced by ERA. ET-1 immunostaining was localized to macrophage-rich regions in aneurysmal vessels. ERA did not prevent AngII-induced aneurysm formation but instead may have increased aneurysm incidence. In AngII-treated animals with aneurysms, ERA had a profound effect on the non-aneurysmal thoracic aorta via increasing wall thickness, collagen/elastin ratio, wall stiffness, and viscous responses. These observations were confirmed in acute in vitro collagen sheet production models in which ERA inhibited AngII's dose-dependent effect on collagen type 1 α 1 (COL1A1) gene transcription. However, chronic treatment reduced matrix metalloproteinase 2 mRNA expression but enhanced COL3A1, tissue inhibitor of metalloproteinase 1 (TIMP-1), and TIMP-2 mRNA expressions. These data confirm a role for the ET system in AngII-accelerated atherosclerosis but suggest that ERA therapy is not protective against the formation of AngII-induced aneurysms and can paradoxically stimulate a chronic arterial matrix remodeling response.
authors: Terrence Donnelly Research Laboratories, Division of Cardiology, St. Michael's Hospital, Toronto, Ontario, Canada.
authors: Renée S
authors: RS
authors: Suen
authors: Sarah N
authors: SN
authors: Rampersad
authors: Duncan J
authors: DJ
authors: Stewart
authors: David W
authors: DW
authors: Courtman
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000502:physiology; D001014:Aortic Aneurysm / Q000139:chemically induced*; D001057:Apolipoproteins E; D050197:Atherosclerosis / Q000139:chemically induced*; D001696:Biomechanical Phenomena; D000077300:Bosentan; D002317:Cardiovascular Agents / Q000494:pharmacology; D002448:Cell Adhesion; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D019012:Integrin beta1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D013312:Stress, Physiological; D013449:Sulfonamides / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000009:adverse effects*
chemical_list: D000959:Antihypertensive Agents; D001057:Apolipoproteins E; D002317:Cardiovascular Agents; D019332:Endothelin-1; D019012:Integrin beta1; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D007371:Interferon-gamma; D003094:Collagen; D000077300:Bosentan