verbatim): Progressive ventricular enlargement following myocardial infarction (MI) remains an important cause of congestive heart failure. Recent studies indicate that matrix metalloproteinases (MMPs) participate in multiple aspects of left ventricular remodeling. Our laboratory has demonstrated that broad MMP inhibition in mice attenuates ventricular dilation following MI. Furthermore, we have now demonstrated that mice with targeted deletion of MMP-9, an enzyme overexpressed in many cells following myocardial infarction, leads to decreased LV dilation and a profound change in myocardial fibrosis after MI. Thus, MMPs may mediate LV remodeling, but with surprising and unanticipated effects. Exploration of this process in mice with genetic alterations in matrix metabolism provides the opportunity for improved understanding of the mechanisms of LV remodeling.
In Specific Aim 1, we will study mice with specific defects in collagen metabolism, including mice with cleavage-resistant collagen as well as mice deficient in MMP-13. We will also study MMP-9 null mice, to address the important question of long-term effects of MMP-9 deletion on LV function after MI. Data from Specific Aim I will be useful for Specific Aim 2, which will investigate ischemia/reperfusion, a process associated with an influx of matrix-degrading leukocytes early after MI.
In Specific Aim 3, we will investigate the potential mechanism of MMP regulation of LV remodeling using bone marrow transplantation. These experiments will allow us to test hypotheses that cells of bone marrow origin mediate specific effects. Finally, in Specific Aim 4, we present new data indicating that MMP substrates may accumulate in both the normal ventricle and the post-infarct ventricle when MMPs are deleted. The potential in vivo substrates for MMPs are of paramount importance in understanding LV remodeling as well as many normal developmental processes, but until recently, the techniques for identification of these substrates have not been available. We will use the emerging technology of proteomics to identify substrates for metalloproteinases that may participate in LV remodeling.
| Lindsey, Merry L; Escobar, G Patricia; Dobrucki, Lawrence W et al. (2006) Matrix metalloproteinase-9 gene deletion facilitates angiogenesis after myocardial infarction. Am J Physiol Heart Circ Physiol 290:H232-9 |
| Lindsey, Merry L; Yoshioka, Jun; MacGillivray, Catherine et al. (2003) Effect of a cleavage-resistant collagen mutation on left ventricular remodeling. Circ Res 93:238-45 |
| Lindsey, Merry L; Gannon, Joseph; Aikawa, Masanori et al. (2002) Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction. Circulation 105:753-8 |
