Macrophage overexpression of matrix metalloproteinase-9 in aged mice improves diastolic physiology and cardiac wound healing following myocardial infarction

Matrix metalloproteinase (MMP)-9 increases in the myocardium with advanced age and after MI. Because young transgenic (TG) mice overexpressing human MMP-9 only in macrophages mice show better outcomes post-MI, while aged TG mice show a worse aging phenotype, we wanted to evaluate the combination effect to see if the detrimental effect of aging counteracted the benefits of macrophage MMP-9 overexpression. We used 17-28 month old male and female C57BL/6J wild type (WT) mice and TG mice (n = 10-21/group) to evaluate the effects of aging superimposed on MI. Despite similar infarct areas and mortality rates at day (D) 7 post-MI, TG aging mice showed improved diastolic properties and remodeling index compared to WT (both P<0.05). Macrophage numbers were higher in TG compared to WT at both D0 and D7 post-MI, and the post-MI increase was due to elevated CD18 protein levels (all P<0.05). RNA-seq analysis of cardiac macrophages isolated from D7 post-MI infarcts identified 1,276 statistically different genes (994 increased and 282 decreased in TG, all P<0.05). Reduced vascular endothelial growth factor-A (VEGFA), platelet-derived growth factor subunit A (Pdgfa), and transforming growth factor beta 3 (Tgfb3) along with elevated tissue inhibitor of MMP-4 (Timp4) macrophage expression reveal mechanisms of indirect downstream effects on fibroblasts and neovascularization. While collagen accumulation was enhanced in TG compared to WT at both D0 and D7 post-MI (P<0.05 for both), the post-MI collagen cross-linking ratio was higher in the WT (P<0.05), consistent with increased diastolic volumes. Vessel numbers (by GSL-I lectin staining) were decreased in the TG compared to WT at both D0 and D7 post-MI (P<0.05 for both). In conclusion, macrophage-derived MMP-9 improved post-MI cardiac wound healing through direct and indirect mechanisms to improve diastolic physiology and remodeling.