Deficiency of MMP1a (Matrix Metalloprotease 1a) Collagenase Suppresses Development of Atherosclerosis in Mice Translational Implications for Human Coronary Artery Disease

OBJECTIVE: Destruction of arterial collagen allows monocyte and macrophage infiltration leading to atherosclerotic plaque formation, but it is not clear what role the MMP1 (matrix metalloprotease 1) collagenase plays in this process in vivo. To define the specific contribution of MMP1 to atherosclerotic plaque burden and pathogenesis, we generated ApoE(-/-) mice deficient in the human MMP1 ortholog, MMP1a. APPROACH AND RESULTS: After 12 to 16 weeks of Western diet, genetic loss of MMP1a resulted in a significant 50% reduction in total aortic plaque burden compared with control ApoE(-/-) mice. MMP1a deficiency led to significant reductions in plaque monocytes/macrophages, SMCs (smooth muscle cells), and necrosis, with increases in collagen content. Collagen invasion of oxidized-LDL (low-density lipoprotein) activated peripheral blood mononuclear cells from MMP1a-deficient mice was markedly attenuated and was similar to suppressive effects with pharmacological inhibitors of MMP1 and its receptor, PAR1 (protease-activated receptor 1). Patients with coronary artery disease and acute coronary syndrome undergoing cardiac catheterization in the TRIP-PCI trial (Thrombin Receptor Inhibitory Pepducin-Percutaneous Coronary Intervention) were evaluated for circulating levels of all 3 major secreted collagenases, MMP1, MMP8, and MMP13 and total number of coronary lesions with >= 50% stenosis (coronary artery disease burden). MMP1 was significantly (P<0.001) higher by 19-fold and 5.7-fold relative to MMP13 and MMP8, respectively. MMP1 correlated with stenotic coronary artery disease burden, TNF alpha (tumor necrosis factor alpha) levels, and was co-expressed with PAR1 on monocytes. Treatment of patients with the PAR1 inhibitor, PZ-128, prevented a drop in monocytes following coronary catheterization, an acute protective effect that was reproduced in mice undergoing cardiac ischemia reperfusion. CONCLUSIONS: These data provide evidence for an important role for the MMP1a collagenase in atherosclerotic lesion development and leukocyte behavior and validate MMP1 as a compelling target in patients with coronary artery disease/acute coronary syndrome.

Automated summary

Deficiency of MMP1a gene resulted in a significant reduction in aortic plaque burden, decreasing monocytes/macrophages, smooth muscle cells, and necrosis, while increasing collagen content. High levels of MMP1 were correlated with stenotic coronary artery disease burden, suggesting its potential as a target for patients with coronary artery disease/acute coronary syndrome.