Our data support cholesterol-independent causal relationships between estrogen, oxidized LDL-induced secretion of macrophage MMP12, and arterial stiffness that protect against atherosclerosis in females and emphasize that reduced MMP12 functionality can confer atheroprotection to males.
The main pathologic role of MMP-12 overexpression was suggested to be associated with pathogenesis mechanism of inflammatory respiratory diseases and atherosclerosis.
In a population cohort, we found that individuals homozygous for the MMP12 low expression allele had higher plasma fibrinogen levels (2.95 mg/mL compared with 2.61 mg/mL in other individuals, p=0.029) and increased risk of advanced atherosclerosis [odds ratio 6.3 (95% CI 1.9-20.8), p=0.003] and myocardial infarction [hazard ratio 5.6 (95% CI 1.7-18.3), p=0.005].
Exposure of ApoE-/- mice to TCDD caused a time-dependent progression of atherosclerosis, which was associated with induction of inflammatory genes, including interleukin-8, as well as F4/80 and matrix metalloproteinase-12.
Through screening expression patterns of typical genes involved in atherosclerosis and foam cell generation, we could demonstrate that mRNA levels of cyclooxygenase-2, interleukin 1beta, and tumor necrosis factor-alpha were increased in a time- and dose-dependent manner in U937 macrophages treated with TCDD, like oxLDL, and that these changes accompanied significantly elevated levels of matrix-degrading metalloproteinases (MMP)-1, MMP-3, MMP-12, and MMP-13.
Human metalloelastase (MMP-12) is an MMP, the expression of which has so far been documented in macrophages associated with atherosclerosis, wound repair, and certain cancers.