Matrix Metalloproteinase-28 Deletion Exacerbates Cardiac Dysfunction and Rupture Following Myocardial Infarction in Mice by Inhibiting M2 Macrophage Activation
Rationale: Matrix metalloproteinase (MMP)-28 regulates the inflammatory and extracellular matrix (ECM) responses in cardiac aging, but the roles of MMP-28 after myocardial infarction (MI) have not been explored.
Objective: To determine the impact of MMP-28 deletion on post-MI remodeling of the left ventricle (LV)
Methods and Results: Adult C57BL/6J wild type (WT, n=76) and MMP null (MMP-28-/-, n=86) mice of both sexes were subjected to permanent coronary artery ligation to create MI. MMP-28 expression decreased post-MI, and its cell source shifted from myocytes to macrophages. MMP-28 deletion increased day 7 mortality as a result of increased cardiac rupture post-MI. MMP-28-/- mice exhibited larger LV volumes, worse LV dysfunction, a worse LV remodeling index, and increased lung edema. Plasma MMP-9 levels were unchanged in the MMP-28-/- mice but increased in WT mice at day 7 post-MI. The mRNA levels of inflammatory and ECM proteins were attenuated in the infarct regions of MMP-28-/- mice, indicating reduced inflammatory and ECM responses. M2 macrophage activation was impaired when MMP-28 was absent. MMP-28 deletion also led to decreased collagen deposition and fewer myofibroblasts. Collagen cross-linking was impaired, due to decreased expression and activation of lysyl oxidase in the infarcts of MMP-28-/- mice. The LV tensile strength at day 3 post-MI, however, was similar between the two genotypes
Conclusions: MMP-28 deletion aggravated MI induced LV dysfunction and rupture, due to defective inflammatory response and scar formation by suppressing M2 macrophage activation.
- macrophage phenotype
- myocardial infarction
- matrix metalloproteinases
- infarct remodeling
- Received November 12, 2012.
- Revision received December 15, 2012.
- Accepted December 19, 2012.
- Copyright © 2012, Circulation Research