Matrix metalloproteinase 7 deficiency acts as a protective effect against vascular dysfunction during atherosclerosis

Abstract

Abstract Matrix metalloproteinase 7 (MMP-7), a zinc-dependent endopeptidase, plays a pivotal role in extracellular matrix remodeling. Its induction is associated with the pathogenesis of atherosclerosis. The current study aimed to investigate the role of MMP-7 in atherosclerosis development, by examining the plasma lipid profile, as well as vascular responses, expression levels of signaling molecules and enzyme activities in aortae of wildtype and apolipoprotein E-deficient (ApoE-/-) mice with and without genetic deletion of MMP-7. In isolated aortae, MMP-7 deficiency exhibited minimal influence on vascular responses in mice with ApoE but abolished cyclooxygenase (COX)-mediated endothelium-dependent contractions to acetylcholine in ApoE-/- mice fed a high-fat diet, an effect independent of the duration of the high-fat diet and sex. Moreover, MMP-7 deficiency attenuated atherosclerotic lesion size in aortae of ApoE-/- mice without significantly altering plasma triglyceride and LDL levels, indicating that the protective effects of MMP-7 deficiency against atherogenesis are not mediated through changes in lipid profiles. Additionally, a sex difference was observed in the vascular effects of MMP-7, which increased the sensitivity of vascular smooth muscle to TP- receptor-mediated contractions in female but not in male ApoE-/- mice. In aortae of male ApoE-/- mice, compared with the wildtype, fed with high-fat diet, MMP-7 level was upregulated; this upregulation was associated with increased activity of phospholipase A2 (PLA2), elevated COX-2 level, enhanced oxidative stress, and augmented production of prostanoids. Moreover, the COX-mediated endothelium-dependent contractions to acetylcholine, present in aortae of ApoE-/- mice with MMP-7 but not in those without MMP-7, were abolished by inhibitors of PLA2, thromboxane-prostanoid (TP) receptors and MMP. These findings suggest that MMP-7 contributes to endothelial dysfunction in atherosclerosis by promoting the production of vasoconstrictor prostanoids through the PLA2/COX-2 pathway, leading to the activation of TP receptor to cause vasoconstriction. In addition, MMP-7 deficiency reduced the degree of senescence and the levels of inflammatory cytokines and adhesion molecules in aortae of male ApoE-/- mice fed with high-fat diet. RNA sequencing data analysis revealed that the differentially expressed genes in ApoE-/-MMP-7-/- mouse aortae, when compared to ApoE-/- but not to the wildtype, were enriched in pathways related to immune and inflammatory responses. Furthermore, the key signaling proteins in the NF-κB, PI3K/AKT, and MAPK/ERK pathways were activated in aortae of ApoE-/- mice with MMP-7, and their activation was reduced in ApoE-/- mice without MMP-7. These findings, therefore, indicate that MMP-7 promotes cellular senescence and vascular inflammation, through activation of the NF-κB, PI3K/AKT, and MAPK/ERK, during the development of atherosclerosis. In conclusion, this study demonstrates that MMP-7 contributes to endothelial dysfunction and atherosclerosis development in hyperlipidemic mice. The protective effects of MMP-7 deficiency against vascular dysfunction are mediated through the attenuation of COX-mediated endothelium-dependent contractions, cellular senescence, and vascular inflammation. These findings provide novel insights into the role of MMP-7 in the pathogenesis of atherosclerosis and suggest that inhibition or downregulation of MMP-7 may serve as a potential therapeutic strategy for preventing vascular dysfunction and atherosclerosis progression.