Mechanisms of induction, activation, and trafficking of myocardial membrane type-1 matrix metalloproteinase in ischemia and reperfusion

Left ventricular (LV) dysfunction and local extracellular matrix (ECM) remodeling can occur in several cardiovascular disease states including myocardial infarction, following myocardial ischemia and reperfusion (I/R), and with pressure overload. Matrix metalloproteinases, or MMPs, are a family of matrix degrading enzymes that have been implicated in this process. One specific MMP, membrane type-1 matrix metalloproteinase (MT1-MMP), has been shown previously to be increased in human heart failure. MT1-MMP is a significant MMP type due to the fact that it has multiple functions including local ECM degradation, activation of other MMP types, and processing of other bioactive molecules including growth factors and cytokines.; Because MT1-MMP is able to initiate a proteolytic cascade through activation of other MMP types and growth factors/cytokines, this enzyme may significantly influence myocardial biology. Biological stimuli operative in cardiovascular diseases can also influence MT1-MMP abundance and activity. For example, cytokines, oxidative stress and endothelin-1 (ET), which are all elevated with I/R, have all been demonstrated to alter MT1-MMP abundance/activity in other systems. Therefore, the objectives of this project were to (1) demonstrate interstitial activity of MT1-MMP in a porcine model of I/R using a validated in vivo system, (2) determine the upstream signaling mechanisms resulting in MT1-MMP activation during I/R and (3) establish an in vivo method for real-time MMP activity measurement in porcine myocardium. Collectively, these studies demonstrated that MT1-MMP activity is significantly increased with I/R and that regulatory mechanisms such as post-translational modification and trafficking likely contribute to changes in activity levels. Furthermore, these studies clearly demonstrate that ET and angiotensin II, which are altered in cardiovascular disease states, influence MMP activity in the porcine myocardial interstitium. Identifying interventional strategies that would decrease the contribution of MT1-MMP in LV dysfunction and subsequent LV remodeling would hold therapeutic potential in multiple cardiovascular disease states.