Macrophage overexpression of matrix metalloproteinase-9 in aged mice improved diastolic properties and remodeling index 7 days post-myocardial infarction compared with wild-type mice (P<0.05).
Does macrophage overexpression of matrix metalloproteinase-9 improve diastolic physiology and cardiac wound healing in aged mice after myocardial infarction?
Macrophage-derived MMP-9 overexpression in aged mice improves post-myocardial infarction cardiac wound healing, leading to better diastolic physiology and left ventricular remodeling.
p-value: p=<0.05
Matrix metalloproteinase (MMP)-9 increases in the myocardium with advanced age and after myocardial infarction (MI). Because young transgenic (TG) mice overexpressing human MMP-9 only in macrophages show better outcomes post-MI, whereas aged TG mice show a worse aging phenotype, we wanted to evaluate the effect of aging superimposed on MI to see if the detrimental effect of aging counteracted the benefits of macrophage MMP-9 overexpression. We used 17- to 28-mo-old male and female C57BL/6J wild-type (WT) and TG mice ( n = 10–21 mice/group) to evaluate the effects of aging superimposed on MI. Despite similar infarct areas and mortality rates at day 7 post-MI, aging TG mice showed improved diastolic properties and remodeling index compared with WT mice (both P < 0.05). Macrophage numbers were higher in TG than WT mice at days 0 and 7 post-MI, and the post-MI increase was due to elevated cluster of differentiation 18 protein levels (all P < 0.05). RNA sequencing analysis of cardiac macrophages isolated from day 7 post-MI infarcts identified 1,276 statistically different (all P < 0.05) genes (994 increased and 282 decreased in TG mice). Reduced expression of vascular endothelial growth factor A, platelet-derived growth factor subunit A, and transforming growth factor-β 3 , along with elevated expression of tissue inhibitor of MMP-4, in macrophages revealed mechanisms of indirect downstream effects on fibroblasts and neovascularization. While collagen accumulation was enhanced in TG mice compared with WT mice at days 0 and 7 post-MI ( P < 0.05 for both), the post-MI collagen cross-linking ratio was higher in WT mice ( P < 0.05), consistent with increased diastolic volumes. Vessel numbers by Griffonia ( Bandeiraea) simplicifolia lectin I staining were decreased in TG mice compared with WT mice at days 0 and 7 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. NEW & NOTEWORTHY Aging mice with macrophage overexpression of matrix metalloproteinase-9 have increased macrophage numbers 7 days after myocardial infarction, resulting in improved diastolic physiology and left ventricular remodeling through effects on cardiac wound healing.
Meschiari et al. (Sat,) conducted a other in Myocardial infarction. Macrophage overexpression of human MMP-9 vs. Wild-type (WT) mice was evaluated on Diastolic properties and remodeling index (p=<0.05). Macrophage overexpression of matrix metalloproteinase-9 in aged mice improved diastolic properties and remodeling index 7 days post-myocardial infarction compared with wild-type mice (P<0.05).