Myocardial Infarction Superimposed on Aging: MMP-9 Deletion Promotes M2 Macrophage Polarization

In this study, we examined the combined effect of aging and myocardial infarction on left ventricular remodeling, focusing on matrix metalloproteinase (MMP)-9-dependent mechanisms. We enrolled 55 C57BL/6J wild type (WT) and 85 MMP-9 Null (Null) mice of both sexes at 11–36 months of age and evaluated their response at Day 7 post–myocardial infarction. Plasma MMP-9 levels positively linked to age in WT mice ( r = .46, p = .001). MMP-9 deletion improved survival (76% for WT vs 88% for Null, p = .021). Post–myocardial infarction, there was a progressive increase in left ventricular dilation with age in WT but not in Null mice. By inflammatory gene array analysis, WT mice showed linear age-dependent increases in three different proinflammatory genes ( C3, CCl4 , and CX3CL1 ; all p < .05), whereas Null mice showed increases in three proinflammatory genes ( CCL5, CCL9 , and CXCL4 ; all p < .05) and seven anti-inflammatory genes ( CCL1, CCL6, CCR1, IL11, IL1r2, IL8rb , and Mif ; all p < .05). Compared with WT, macrophages isolated from Null left ventricle infarct demonstrated enhanced expression of anti-inflammatory M2 markers CD163, MRC1, TGF-β1 , and YM1 (all p < .05), without affecting proinflammatory M1 markers. In conclusion, MMP-9 deletion stimulated anti-inflammatory polarization of macrophages to attenuate left ventricle dysfunction in the aging post–myocardial infarction.