Matrix remodeling in experimental and human heart failure: a possible regulatory role for TIMP-3

1 Division of Cardiac Surgery, Toronto General Research Institute, University of Toronto, Toronto General Hospital, Toronto M5G 2C4; and 2 Roy and Ann Foss Interventional Cardiology Research Program, Division of Cardiology, Terrence Donnelly Heart Centre, University of Toronto, St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8 In the failing heart, an imbalance in matrix metalloproteinases (MMPs) and their biological regulators, the tissue inhibitors of MMPs (TIMPs), may result in cardiac dilatation from matrix degradation. We hypothesized that a reduction of myocardial TIMP-3 is associated with adverse matrix remodeling in both human and experimental heart failure. Cardiomyopathic hamsters at age 15 wk (normal), 25 wk (compensated stage), and 35 wk (overt failure) were compared with age-matched normal controls. MMP activity (gelatinase bioassay) was increased in cardiomyopathic hearts ( P = 0.03) and peaked during the transition to overt heart failure. TIMP-3 content (immunoblot) was decreased compared with normal controls (74 ± 5% at 25 wk, 69 ± 10% at 35 wk; P = 0.001) and its reduction was associated with increased MMP activity ( r = 0.6; P = 0.004). TIMP-1 increased progressively ( P = 0.001), whereas TIMP-2, TIMP-4, and MMP protein levels were unchanged. Myocardial collagen (hydroxyproline content) increased with time during the progression to end-stage cardiac failure ( P