title: Prevention of TGFβ induction attenuates angII-stimulated vascular biglycan and atherosclerosis in Ldlr-/- mice.
abstract: Angiotensin II (angII) accelerates atherosclerosis, but the mechanisms are not fully understood. The aim of this study was to determine whether TGFβ is required for angII-induced atherosclerosis. Ldlr-null mice fed a normal chow diet were infused with angII or saline for 28 days. A single injection of TGFβ neutralizing antibody 1D11 (2 mg/kg) prevented angII-induction of TGFβ1 levels, and strikingly attenuated angII-induced accumulation of aortic biglycan content. To study atherosclerosis, mice were infused with angII or saline for 4 weeks, and then fed Western diet for a further 6 weeks. 1D11 had no effect on systolic blood pressure or plasma cholesterol; however, angII-infused mice that received 1D11 had reduced atherosclerotic lesion area by 30% (P < 0.05). Immunohistochemical analyses demonstrated that angII induced both lipid retention and accumulation of biglycan and perlecan which colocalized with apoB. 1D11 strikingly reduced the effect of angII on biglycan but not perlecan. 1D11 decreased total collagen content (P < 0.05) in the lesion area without changing plaque inflammation markers (CD68 and CD45). Thus, this study demonstrates that neutralization of TGFβ attenuated angII stimulation of biglycan accumulation and atherogenesis in mice, suggesting that TGFβ-mediated biglycan induction is one of the mechanisms underlying angII-promoted atherosclerosis.
authors.affiliation: Division of Endocrinology and Molecular Medicine, University of Kentucky, Lexington, KY; Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY; and.
authors.forename: Tao
authors.initials: T
authors.lastname: Tang
authors.affiliation: Division of Endocrinology and Molecular Medicine, University of Kentucky, Lexington, KY; Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY; and.
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Wilson
authors.affiliation: Division of Endocrinology and Molecular Medicine, University of Kentucky, Lexington, KY; Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY; and.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Thompson
authors.affiliation: Division of Endocrinology and Molecular Medicine, University of Kentucky, Lexington, KY.
authors.forename: Christina
authors.initials: C
authors.lastname: Nelson
authors.affiliation: Division of Endocrinology and Molecular Medicine, University of Kentucky, Lexington, KY.
authors.forename: Meghan H
authors.initials: MH
authors.lastname: Yoder
authors.affiliation: Division of Endocrinology and Molecular Medicine, University of Kentucky, Lexington, KY; Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY; and; Department of Veterans Affairs, Lexington, KY. Electronic address: Lisa.Tannock@uky.edu.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Tannock
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D058578:Biglycan / Q000096:biosynthesis*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011973:Receptors, LDL / Q000172:deficiency* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D058578:Biglycan; D011973:Receptors, LDL; D016212:Transforming Growth Factor beta; D000804:Angiotensin II
keywords: TGFβ neutralizing antibody; angiotensin II; atherosclerosis initiation; biglycan-apoB colocalization; low density lipoprotein retention; proteoglycans; renin-angiotensin system