CHI-SHENG HUNGChou C.-H.CHE-WEI LIAOLin Y.-T.Wu X.-M.Chang Y.-Y.YING-HSIEN CHENVIN-CENT WUMING-JAI SUYI-LWUN HOMING-FONG CHENYEN-HUNG LINKWAN-DUN WU2020-09-282020-09-2820160194-911Xhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84968608604&doi=10.1161%2fHYPERTENSIONAHA.115.06768&partnerID=40&md5=df202de1595dc5b3ab2d1ca1b2fc0b36https://scholars.lib.ntu.edu.tw/handle/123456789/515052Aldosterone induces myocardial fibrosis. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a key factor of myocardial fibrosis. This study tested the hypothesis that aldosterone induces TIMP-1 expression and contributes to the fibrotic process. We prospectively enrolled 54 patients with primary aldosteronism, and measured plasma TIMP-1 and echocardiographic parameters. In the cell study, we investigated the possible molecular mechanism by which aldosterone induces TIMP-1 secretion and the effects on collagen accumulation. In the animal study, we measured serum TIMP-1 levels, cardiac TIMP-1 levels, and cardiac structure in an aldosterone infusion mouse model using implantation of aldosterone pellets. In patients with primary aldosteronism, plasma TIMP-1 was correlated with 24-hour urinary aldosterone, left ventricular mass, and impairment of left ventricular diastolic function. In human cardiac fibroblasts, TIMP-1 protein and mRNA expressions were significantly increased by aldosterone through the glucocorticoid receptor/PI3K/Akt/nuclear factor-κB pathway. TIMP-1 small-interfering RNA significantly reduced aldosterone-induced collagen accumulation, and aldosterone did not alter the levels of collagen1a1 or matrix metalloproteinase-1 mRNA. The aldosterone-induced TIMP-1 expression was inversely related to matrix metalloproteinase-1 activity. Furthermore, in the animal model, the serum and cardiac levels of TIMP-1 were significantly elevated in the mice that received aldosterone infusion. This elevation was blocked by RU-486 but not by eplerenone, suggesting that the effect was through glucocorticoid receptors. In a long-term aldosterone infusion model, serum TIMP-1 was associated with serum aldosterone level, cardiac structure, and fibrosis. In conclusion, aldosterone induced TIMP-1 expression in vivo and in vitro. This increased TIMP-1 expression resulted in enhanced collagen accumulation via the suppression of matrix metalloproteinase-1 activity. ? 2016 American Heart Association, Inc.[SDGs]SDG3journal article10.1161/HYPERTENSIONAHA.115.06768271130512-s2.0-84968608604