Aldosterone Induces Tissue Inhibitor of Metalloproteinases-1 Expression and Further Contributes to Collagen Accumulation: From Clinical to Bench Studies.
Aldosterone 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.
From the Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan (C.-S.H., Y.-H.C., Y.-L.H.); Departments of Internal Medicine (C.-S.H., V.-C.W., Y.-L.H., M.-F.C., K.-D.W., Y.-H.L.) and Obstetrics and Gynecology (C.-H.C.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan (C.-W.L., Y.-T.L.); Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan (X.-M.W.); Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Y.-Y.C.); and Institute of Pharmacology, National Taiwan University Medical College, Taipei, Taiwan (M.-J.S.).
Chi-Sheng
CS
Hung
From the Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan (C.-S.H., Y.-H.C., Y.-L.H.); Departments of Internal Medicine (C.-S.H., V.-C.W., Y.-L.H., M.-F.C., K.-D.W., Y.-H.L.) and Obstetrics and Gynecology (C.-H.C.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan (C.-W.L., Y.-T.L.); Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan (X.-M.W.); Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Y.-Y.C.); and Institute of Pharmacology, National Taiwan University Medical College, Taipei, Taiwan (M.-J.S.).
Chia-Hung
CH
Chou
From the Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan (C.-S.H., Y.-H.C., Y.-L.H.); Departments of Internal Medicine (C.-S.H., V.-C.W., Y.-L.H., M.-F.C., K.-D.W., Y.-H.L.) and Obstetrics and Gynecology (C.-H.C.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan (C.-W.L., Y.-T.L.); Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan (X.-M.W.); Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Y.-Y.C.); and Institute of Pharmacology, National Taiwan University Medical College, Taipei, Taiwan (M.-J.S.).
Che-Wei
CW
Liao
From the Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan (C.-S.H., Y.-H.C., Y.-L.H.); Departments of Internal Medicine (C.-S.H., V.-C.W., Y.-L.H., M.-F.C., K.-D.W., Y.-H.L.) and Obstetrics and Gynecology (C.-H.C.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan (C.-W.L., Y.-T.L.); Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan (X.-M.W.); Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Y.-Y.C.); and Institute of Pharmacology, National Taiwan University Medical College, Taipei, Taiwan (M.-J.S.).
Yen-Tin
YT
Lin
From the Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan (C.-S.H., Y.-H.C., Y.-L.H.); Departments of Internal Medicine (C.-S.H., V.-C.W., Y.-L.H., M.-F.C., K.-D.W., Y.-H.L.) and Obstetrics and Gynecology (C.-H.C.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan (C.-W.L., Y.-T.L.); Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan (X.-M.W.); Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Y.-Y.C.); and Institute of Pharmacology, National Taiwan University Medical College, Taipei, Taiwan (M.-J.S.).
Xue-Ming
XM
Wu
From the Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan (C.-S.H., Y.-H.C., Y.-L.H.); Departments of Internal Medicine (C.-S.H., V.-C.W., Y.-L.H., M.-F.C., K.-D.W., Y.-H.L.) and Obstetrics and Gynecology (C.-H.C.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan (C.-W.L., Y.-T.L.); Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan (X.-M.W.); Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Y.-Y.C.); and Institute of Pharmacology, National Taiwan University Medical College, Taipei, Taiwan (M.-J.S.).
Yi-Yao
YY
Chang
From the Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan (C.-S.H., Y.-H.C., Y.-L.H.); Departments of Internal Medicine (C.-S.H., V.-C.W., Y.-L.H., M.-F.C., K.-D.W., Y.-H.L.) and Obstetrics and Gynecology (C.-H.C.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan (C.-W.L., Y.-T.L.); Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan (X.-M.W.); Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Y.-Y.C.); and Institute of Pharmacology, National Taiwan University Medical College, Taipei, Taiwan (M.-J.S.).
Ying-Hsien
YH
Chen
From the Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan (C.-S.H., Y.-H.C., Y.-L.H.); Departments of Internal Medicine (C.-S.H., V.-C.W., Y.-L.H., M.-F.C., K.-D.W., Y.-H.L.) and Obstetrics and Gynecology (C.-H.C.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan (C.-W.L., Y.-T.L.); Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan (X.-M.W.); Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Y.-Y.C.); and Institute of Pharmacology, National Taiwan University Medical College, Taipei, Taiwan (M.-J.S.).
Vin-Cent
VC
Wu
From the Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan (C.-S.H., Y.-H.C., Y.-L.H.); Departments of Internal Medicine (C.-S.H., V.-C.W., Y.-L.H., M.-F.C., K.-D.W., Y.-H.L.) and Obstetrics and Gynecology (C.-H.C.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan (C.-W.L., Y.-T.L.); Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan (X.-M.W.); Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Y.-Y.C.); and Institute of Pharmacology, National Taiwan University Medical College, Taipei, Taiwan (M.-J.S.).
Ming-Jai
MJ
Su
From the Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan (C.-S.H., Y.-H.C., Y.-L.H.); Departments of Internal Medicine (C.-S.H., V.-C.W., Y.-L.H., M.-F.C., K.-D.W., Y.-H.L.) and Obstetrics and Gynecology (C.-H.C.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan (C.-W.L., Y.-T.L.); Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan (X.-M.W.); Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Y.-Y.C.); and Institute of Pharmacology, National Taiwan University Medical College, Taipei, Taiwan (M.-J.S.).
Yi-Lwun
YL
Ho
From the Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan (C.-S.H., Y.-H.C., Y.-L.H.); Departments of Internal Medicine (C.-S.H., V.-C.W., Y.-L.H., M.-F.C., K.-D.W., Y.-H.L.) and Obstetrics and Gynecology (C.-H.C.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan (C.-W.L., Y.-T.L.); Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan (X.-M.W.); Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Y.-Y.C.); and Institute of Pharmacology, National Taiwan University Medical College, Taipei, Taiwan (M.-J.S.).
Ming-Fong
MF
Chen
From the Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan (C.-S.H., Y.-H.C., Y.-L.H.); Departments of Internal Medicine (C.-S.H., V.-C.W., Y.-L.H., M.-F.C., K.-D.W., Y.-H.L.) and Obstetrics and Gynecology (C.-H.C.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan (C.-W.L., Y.-T.L.); Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan (X.-M.W.); Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Y.-Y.C.); and Institute of Pharmacology, National Taiwan University Medical College, Taipei, Taiwan (M.-J.S.).
Kwan-Dun
KD
Wu
From the Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan (C.-S.H., Y.-H.C., Y.-L.H.); Departments of Internal Medicine (C.-S.H., V.-C.W., Y.-L.H., M.-F.C., K.-D.W., Y.-H.L.) and Obstetrics and Gynecology (C.-H.C.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan (C.-W.L., Y.-T.L.); Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan (X.-M.W.); Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Y.-Y.C.); and Institute of Pharmacology, National Taiwan University Medical College, Taipei, Taiwan (M.-J.S.). austinr34@gmail.com.
Yen-Hung
YH
Lin
D000450:Aldosterone / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D006929:Hyperaldosteronism / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*
D012333:RNA, Messenger; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D000450:Aldosterone; D003094:Collagen; D020781:Matrix Metalloproteinase 1
aldosterone; collagen; fibroblasts; glucocorticoid receptor; tissue inhibitor of metalloproteinases-1