MMP-2: Is too low as bad as too high in the cardiovascular system?

Matrix metalloproteinase-2 (MMP-2) cleaves a broad spectrum of substrates including extracellular matrix components (responsible for normal tissue remodeling) and cytokines (modulators of the inflammatory response to physiological insults such as tissue damage). MMP-2 expression is elevated in many pathologies (e.g., myocardial infarction, hypertensive heart disease, inflammation) where tissue remodeling and inflammatory responses are perturbed. Thus, it has generally been assumed that blockade of MMP-2 activity will yield therapeutic effects. Here, we provide a counter-argument to this dogma based on: a) Preclinical studies on Mmp2 null (Mmp2-/- ) mice subjected to myocardial infarction, hypertensive heart disease or inflammatory conditions. b) Clinical studies on patients with congenital cardiac and bone physiology abnormalities due to inactivating MMP2 gene mutations. Furthermore, we put forward the hypothesis that when MMP-2 activity falls below baseline the bioavailability of pro-inflammatory cytokines normally cleaved and inactivated by MMP-2 increases leading to production of cytokines and cardiac secretion of phospholipase A2 activity into circulation which stimulate systemic inflammation that perturbs lipid metabolism in target organs. Finally, we suggest that insufficient understanding of the consequences of MMP-2 deficiency remains a major factor in the failure of MMP-2 inhibitor-based therapeutic approaches. This paucity of knowledge precludes our ability to effectively intervene in cardiovascular and non-cardiovascular pathologies at the level of MMP-2.