Grant: Operating Grant

Enhanced oxidative stress is common to several cardiac diseases and can damage heart muscle cells, sometimes leading to cell death. This of course can result in heart failure. There are enzymes in heart cells which may be activated as a result of enhanced oxidative stress and contribute to cell injury and death by cutting other proteins into smaller pieces. These enzymes, known as proteases, are very important in cell injury pathways and inhibiting their activity may prevent injury from oxidative stress. This proposal will focus particularly on one such protease, matrix metalloproteinase-2 (MMP-2), which has newly discovered biological roles inside of heart muscle cells which may contribute to cell injury and death. We particularly would like to understand the role of MMP-2 in cell injury and death, and compare its role to other known proteases, as we believe it has distinct undiscovered roles and targets. We will use a combination of approaches including molecular, to cultured heart muscle cells, to intact hearts isolated from rats which have been given treatments to enhance oxidative stress. We will determine if inhibiting MMP-2 will protect the cells and the hearts from cell injury and death resulting from oxidative stress. The relevance of this research is that an entirely new class of inhibitor drugs which target MMP-2 may prove useful for the treatment of a broad range of cardiovascular diseases, as enhanced oxidative stress is common to many.