title: Eplerenone attenuates myocardial fibrosis in the angiotensin II-induced hypertensive mouse: involvement of tenascin-C induced by aldosterone-mediated inflammation.
abstract: Tenascin-C is an extracellular matrix glycoprotein that is supposed to be a profibrotic molecule in various fibrogenic processes. To elucidate its significance for myocardial fibrosis in the hypertensive heart, we used a mouse model with infusion of angiotensin II and examined results by histology, immunohistochemistry, in situ hybridization, and quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). Angiotensin II treatment elevated blood pressure and expression of tenascin-C by interstitial fibroblasts in perivascular fibrotic lesions, and angiotensin II infusion caused accumulation of macrophages. It also upregulated expression of collagen Ialpha2; IIIalpha1; and proinflammatory/profibrotic mediators including transforming growth factor beta (TGFbeta), platelet-derived growth factor alpha (PDGF-A), PDGF-B, and PDGF-receptor alpha, but not IL-1beta and PDGF-receptor beta, in the myocardium. Treatment with an aldosterone receptor antagonist, eplerenone, significantly attenuated angiotensin II-induced fibrosis, expression of tenascin-C, and inflammatory changes without affecting the blood pressure level. In vitro, neither eplerenone nor aldosterone exerted any influence on tenascin-C expression of cardiac fibroblasts, whereas angiotensin II, TGF-beta1, and PDGF significantly upregulated expression of tenascin-C. These results suggest that, in the angiotensin II-induced hypertensive mouse heart: (1) tenascin-C may be involved in the progression of cardiac fibrosis and (2) aldosterone may elicit inflammatory reactions in myocardium, which might, in turn, induce tenascin-C synthesis of fibroblasts through at least 2 pathways mediated by TGF-beta and PDGF-A-B/PDGF-receptor alpha.
authors.affiliation: Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishioka
authors.forename: Maiko
authors.initials: M
authors.lastname: Suzuki
authors.forename: Katsuya
authors.initials: K
authors.lastname: Onishi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takakura
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Inada
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Michiaki
authors.initials: M
authors.lastname: Hiroe
authors.forename: Kyoko
authors.initials: K
authors.lastname: Imanaka-Yoshida
mesh_terms: D000450:Aldosterone / Q000378:metabolism*; D000704:Analysis of Variance; D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D004195:Disease Models, Animal; D000077545:Eplerenone; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018836:Inflammation Mediators / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D019063:Tenascin / Q000096:biosynthesis / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000009:adverse effects
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D000451:Mineralocorticoid Receptor Antagonists; D019063:Tenascin; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone