Plasma concentrations of matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1 and osteopontin reflect severity of heart failure in DOCA-salt hypertensive rat.
The matrix metalloproteinases (MMPs) and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) play a key role in extracellular matrix maintenance and are altered in the failing heart, both in experimental models and in chronic end-stage heart failure in humans. As the common diagnostic markers of heart failure, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) primarily reflect increased pressure loading, determination of soluble, heart-derived MMPs and TIMPs in plasma, as well as the determination of the emerging fibrosis marker osteopontin (OPN) might be valuable tools for detecting heart fibrosis. In this study the effect of spironolactone treatment on plasma MMP-2, TIMP-1 and OPN levels was assessed in a heart failure animal model. Unilaterally nephrectomized Sprague Dawley rats received subcutaneous injection of 100 mg deoxycorticosterone acetate (DOCA) once a week and 1% (w/v) NaCl in drinking water. Blood pressure was monitored weekly and blood samples were collected after 1, 2 and 4 weeks. After 6 weeks, left ventricular contractility (LVC) and heart weight-to-body weight ratio (HW/BW) were assessed. DOCA treatment increased plasma MMP-2, TIMP-1 and OPN concentrations. Alterations of plasma marker levels were correlated with changes of HW/BW and paralleled impaired LVC. Furthermore, beneficial effects of spironolactone treatment were observed. In DOCA-salt hypertensive rats, plasma concentrations of MMP-2, TIMP-1 and OPN reflected heart failure associated with haemodynamic, functional and morphological changes. Based on these findings, it appears reasonable to use plasma markers of fibrosis to monitor the development of heart failure.
Kramer
Frank
F
Institute for Target Discovery-Biomarker, Bayer HealthCare AG, Wuppertal, Germany. frank.kramer@bayerhealthcare.com
Sandner
Peter
P
Klein
Martina
M
Krahn
Thomas
T
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure; D003900:Desoxycorticosterone / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000139:chemically induced / Q000378:metabolism*; D006352:Heart Ventricles / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood*; D009200:Myocardial Contraction; D053495:Osteopontin / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012492:Salts / Q000494:pharmacology*; D013148:Spironolactone / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*
D015415:Biomarkers; D012492:Salts; D019715:Tissue Inhibitor of Metalloproteinase-1; D053495:Osteopontin; D013148:Spironolactone; D003900:Desoxycorticosterone; D020778:Matrix Metalloproteinase 2