Matrix Metalloproteinase-12 Exhibits Context-Dependent Roles in Arterial Disease Remodeling and Inflammation

Maladaptive vascular remodeling, characterized by structural changes in arterial walls, is a hallmark of numerous arterial disorders, including atherosclerosis, aneurysms, and hypertension. This remodeling arises from a complex interplay between chronic inflammation and dysregulated extracellular matrix (ECM) turnover. Current therapeutic strategies often broadly target inflammation or matrix degradation, but lack the precision to address the specific, dynamic mechanisms driving disease progression. Matrix metalloproteinase-12 (MMP-12), also known as macrophage elastase, has emerged as a critical, yet multifaceted, enzyme within this intricate crosstalk, warranting a deeper understanding of its context-specific actions.

This comprehensive review synthesizes current knowledge on Matrix metalloproteinase-12 (MMP-12), detailing its structure, function, and regulation across various arterial diseases. The authors integrated findings from diverse experimental models and clinical settings to elucidate how MMP-12 activity is influenced by the inflammatory milieu, temporal disease stage, and the specific substrate landscape. The review aimed to provide a unifying framework for interpreting divergent observations regarding MMP-12's roles and to identify opportunities and challenges for MMP-12-targeted therapeutic strategies, emphasizing the need for context-specific interpretation of evidence.

The review highlights that MMP-12's role in arterial diseases is highly context-dependent, acting through diverse mechanisms. It functions primarily as a matrix-degrading protease, breaking down key ECM components like elastin, which contributes to vascular weakening and remodeling. Beyond direct matrix degradation, MMP-12 also acts as an amplifier of inflammatory cell recruitment, facilitating the migration of macrophages and other immune cells into the vascular wall, thereby perpetuating the inflammatory cycle. Furthermore, MMP-12 regulates other protease cascades, influencing the activity of various enzymes involved in tissue remodeling and inflammation. In specific settings, MMP-12 can even serve as a homeostatic modulator, contributing to the resolution of inflammation and tissue repair. > The review emphasizes that understanding MMP-12 activity requires interpreting it in relation to the specific inflammatory milieu, the temporal stage of the disease, and the available substrate landscape, explaining previously divergent observations across studies. This multifaceted role underscores the complexity of targeting MMP-12 therapeutically.