Eplerenone attenuates myocardial fibrosis in the angiotensin II-induced hypertensive mouse: Involvement of tenascin-C induced by aldosterone-mediated inflammation
Eplerenone attenuates myocardial fibrosis in the angiotensin II-induced hypertensive mouse: Involvement of tenascin-C induced by aldosterone-mediated inflammation
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DOI：
10.1097/fjc.0b013e318033dfd4
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发表时间：
2007-05-01
影响因子：
3
通讯作者：
Imanaka-Yoshida, Kyoko
中科院分区：
文献类型：
--
作者：
Nishioka, Tomohiro;Suzuki, Maiko;Imanaka-Yoshida, Kyoko
Tenascin-C是一种细胞外基质糖蛋白，在各种纤维化过程中被认为是促纤维化分子。为了阐明其在高血压心脏心肌纤维化中的意义，我们采用输注血管紧张素II的小鼠模型，并通过组织学、免疫组织化学、原位杂交和实时定量逆转录酶聚合酶链反应（RT-PCR）检测结果。血管紧张素II治疗血压升高和血管周围纤维化病变间质成纤维细胞表达tenascin-C，血管紧张素II输注引起巨噬细胞积聚。上调胶原蛋白1 α - 2的表达；III α 1；心肌中的促炎/促纤维化介质包括转化生长因子β (TGF β)、血小板衍生生长因子α (PDGF-A)、PDGF-B和pdgf受体α，但不包括IL-1 β和pdgf受体β。用醛固酮受体拮抗剂eplerenone治疗，可显著减轻血管紧张素ii诱导的纤维化、tenascin-C的表达和炎症变化，而不影响血压水平。在体外，eperenone和醛固酮对心脏成纤维细胞的tenascin-C表达没有任何影响，而血管紧张素II、tgf - β 1和PDGF显著上调tenascin-C的表达。这些结果表明，在血管紧张素ii诱导的高血压小鼠心脏中：(1)tenascin-C可能参与心脏纤维化的进展；(2)醛固酮可能引起心肌炎症反应，这可能反过来通过tgf - α和PDGF-A-B/ pdgf受体α介导的至少2种途径诱导tenascin-C合成成纤维细胞。
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 1 alpha.2; III alpha 1; and proinflammatory/profibrotic mediators including transforming growth factor beta (TGF beta), platelet-derived growth factor alpha (PDGF-A), PDGF-B, and PDGF-receptor alpha, but not IL-1 beta 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-beta 1, 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-alpha and PDGF-A-B/PDGF-receptor alpha.