Matrix Metalloproteinase-28 Deletion Exacerbates Cardiac Dysfunction and Rupture After Myocardial Infarction in Mice by Inhibiting M2 Macrophage Activation

Abstract

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.

Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization

“…For example, macrophage treatment with LPS (1 g/ml) and interferon-␥ (20 ng/ml) increased Tnf␣ and Ccl3 expression 100-fold, whereas SPARC induced 2-fold increases in these two genes (35). Of note, in addition to SPARC increasing Tnf␣ and Ccl3, SPARC also decreased Mrc1 expression by 62%, whereas IL-4, an M2 driver, induces a 3.5-fold increase (35).…”

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

“…In both chronic conditions and myocardial infarction, inflammatory cytokines induce tissue remodeling and degradation of ECM in the myocardium (Gullestad et al, 2012). The loss of ECM can result in a temporary decrease in the passive wall stiffness and increase in diastolic strains in the infarct region, which increase the chance of myocardial wall rupture (Banerjee et al, 2006;Gao et al, 2005;Ma et al, 2013). Deposition of de novo ECM is necessary to maintain structural integrity and requires the switch from inflammatory to profibrotic signaling factors (Frangogiannis, 2014).…”

A Novel Role of Matrix Metalloproteinase-8 in Macrophage Differentiation and Polarization

“…Several other MMPs have been reported to have an effect on M polarization (23,33). A recent study showed that Mmp28 gene inactivation impaired M2-M polarization and resulted in an aggravated cardiac dysfunction after myocardial infarction in mice (23).…”

“…A recent study showed that Mmp28 gene inactivation impaired M2-M polarization and resulted in an aggravated cardiac dysfunction after myocardial infarction in mice (23). Another study showed that loss of MMP28 reduced M2 polarization and protection from bleomycin-induced fibrosis (33).…”

“…M1-and M2 Macrophage Polarization-Both BMM or pM were incubated with 10 ng/ml of IFN-␥ or IL-4 for 48 h to induce M1-and M2 macrophage polarization, respectively, as described previously (23).…”