Project 451652

Myocardial infarction (MI), or heart attack, happens when an artery supplying blood to the heart muscle is clogged, the affected heart muscle dies and is replaced by scar tissue (infarct). The heart tries to compensate for this muscle loss by: 1) recruiting inflammatory cells (scavengers) to clean up the dead cell debris (inflammation), 2) generating new branches/extending the existing branches of the blood vessels to provide new source of blood supply to the infarcted area (angiogenesis), and 3) generating a scar tissue to cover the 'hole' that would otherwise form in the wall of the heart (infarct or fibrosis). These events are mediated by different cell types (inflammatory cells, endothelial cells, fibroblasts) that are present or are recruited to the heart tissue in a time-dependent fashion. ADAM17 (disintegrin and metalloproteinase 17) is a proteinase (enzyme) that is present on the cell membrane of the cells involved in the described processes, and can regulate the function of these cells. ADAM17 is elevated in the heart and plasma of patients with acute MI, and its levels have been linked to adverse outcomes in these patients. We will use mice lacking ADAM17 in each cell type, that will undergo microsurgery to induce MI (an artery is surgically closed off). We will then determine how ADAM17 loss in each cell type affects the outcome of recovery from MI. These experiments will identify the cell type in which ADAM17 deletion can be beneficial, and hence identify a time-window when where ADAM17 inhibition could be beneficial. We will then use a pharmacological ADAM17 inhibitor (PF-05480090, Pfizer), to administer for the duration of the identified time window. This approach for short-term inhibition of ADAM17 will be particularly effective since given the diverse functions of ADAM17, its prolonged inhibition may be associated with side effects.