Infarct in the Heart: What's MMP-9 Got to Do with It?

Abstract

Over the past three decades, numerous studies have shown a strong connection between matrix metalloproteinase 9 (MMP-9) levels and myocardial infarction (MI) mortality and left ventricle remodeling and dysfunction. Despite this fact, clinical trials using MMP-9 inhibitors have been disappointing. This review focuses on the roles of MMP-9 in MI wound healing. Infiltrating leukocytes, cardiomyocytes, fibroblasts, and endothelial cells secrete MMP-9 during all phases of cardiac repair. MMP-9 both exacerbates the inflammatory response and aids in inflammation resolution by stimulating the pro-inflammatory to reparative cell transition. In addition, MMP-9 has a dual effect on neovascularization and prevents an overly stiff scar. Here, we review the complex role of MMP-9 in cardiac wound healing, and highlight the importance of targeting MMP-9 only for its detrimental actions. Therefore, delineating signaling pathways downstream of MMP-9 is critical.

Keywords: extracellular matrix; inflammation; macrophage; matrix metalloproteinases; neutrophil; remodeling.

Figure 1

Temporal profile of MMP-9, leukocytes, and fibroblasts during myocardial infarction wound healing. The left side shows the temporal profile of MMP-9 and the relative abundance of neutrophils, macrophages, B-cells, T-cells, and fibroblasts during inflammation, proliferation and maturation phase. The graphs are based on the current literature [77,78,79,80,81,82,83,84]. The right side shows the cellular source of MMP-9, as well as in vitro stimulators of MMP-9 release and the effect of MMP-9 on different myocardial infarction wound healing processes. IL-1β: Interleukin 1 beta, IL-8: Interleukin 8, MMP-9: Matrix metalloproteinase-9, TNFα: Tumor necrosis alpha, N1: Pro-inflammatory neutrophils, N2: Anti-inflammatory/reparative neutrophils, M1: Pro-inflammatory macrophages, M2: Anti-inflammatory/reparative macrophages, F1: Pro-inflammatory fibroblasts, F2: Anti-inflammatory/reparative fibroblasts. Created with BioRender.com (accessed on 23 March 2021) [85].

Figure 2

MMP-9 roles in inflammation and resolution after myocardial infarction. DAMPs: Danger associated molecular patterns, CD36: Cluster of differentiation 36, CXCL: CXC motif ligand, IL-1β: Interleukin 1 beta, IL-8: Interleukin 8, MMP: Matrix metalloproteinase, PTM: Post-translational modification, TIMP: Tissue inhibitor of metalloproteinases, TGFβ: Transforming growth factor beta. M1: Pro-inflammatory macrophages, M2: Anti-inflammatory/reparative macrophages, F1: Pro-inflammatory fibroblasts, F2: Anti-inflammatory/reparative fibroblasts. Created with BioRender.com (accessed on 23 March 2021) [85].