Myocardial matrix metalloproteinase activity and abundance with congestive heart failure

Abstract

The left ventricular (LV) myocardial collagen matrix has been proposed to participate in the maintenance of LV geometry. Thus alterations in the composition of the LV myocardial collagen matrix may influence LV function. The matrix metalloproteinases (MMPs) are a family of enzymes that contribute to extracellular remodeling in several disease states. However, the types of MMPs expressed in the normal and congestive heart failure (CHF) state and the relation to MMP activity remained unclear. Accordingly, after 3 wk of pacing (240 beats/min), changes in LV function, substrate-specific MMP activity, and MMP subclass abundance were measured in comparison with control pigs ( n = 6). Changes in LV function and geometry were measured by echocardiography; LV end-diastolic dimension increased (3.6 ± 0.1 vs. 6.0 ± 0.1 cm, P < 0.05) and LV fractional shortening decreased (47 ± 1 vs. 15 ± 1%, P < 0.05) compared with controls. Degradation of fibrillar collagen is achieved through the combined action of interstitial collagenase (MMP-1), gelatinase A (MMP-2), and stromelysin (MMP-3) (He, C., S. Wilheilm, A. Pentland, B. Marmer, G. Grant, A. Eisen, and G. Goldberg. Proc. Natl. Acad. Sci. USA 86: 2632–2636, 1989; Woessner, J. FASEB J. 5: 2145–2154, 1991). Accordingly, the relative abundance of specific MMPs (MMP-1, MMP-2, and MMP-3) was examined by immunoblotting. With pacing CHF, the relative abundance for MMP-1 increased to 319 ± 94%, MMP-2 increased to 194 ± 31%, and MMP-3 increased to 493 ± 159% (all P < 0.05). With pacing CHF, LV myocardial zymographic activity for the substrate gelatin increased by 119% ( P < 0.05) and for the substrate collagen III by 153% ( P < 0.05) over controls. Caseinolytic activity also increased with pacing CHF by 139% ( P < 0.05) over controls. In conclusion, LV myocardial MMP activity and abundance increased with pacing-induced CHF. These findings demonstrate that pacing-induced CHF leads to changes in myocardial MMP activity and expression that may be responsible for LV remodeling in CHF.