Grant: Operating Grant

When and artery is clogged, the heart muscle normally supplied by this artery becomes deprived of ixygen and nutrition (ischemic). Re-opening the clogged artery is often a therapeutic solution, but that also triggers a number of cellular and molecular events leading to furhter damaging of the heart muscle, termed 'reperfusion injury'. Many therapies have been applied to prevent this type of injuyr, but they have been unsuccessful. A poorly studied aspect of reperfusion injury in the heart is the adverse remodeling of the extracellular matrix (ECM), the network that connects different cells and vessels in the heart, provides structural support, and also houses a number of signlaing molecules. When the ECM disrupted, these molecules are released and subsequently trigger damaging effects for the heart muscle. The structure of ECM is maintained by a balance in the function of matrix metalloproteases (MMPs) that degrade the ECM proteins, and their inhibitors, TIMPs. We have found that levels of TIMPs are generally reduced in myocardial reperfusion injury. We propose to use genetically modified mice that lack specific TIMPs to determine the function of these molecules in reperfusion injury in the heart. Subsequently, we will aim to prevent this type of injury by replenishing the specific TIMP (or a mixture of TIMPs) in the damaged heart muscle.