Matrix metalloproteinase-2 regulates the expression of tissue inhibitor of matrix metalloproteinase-2

P>1. Matrix metalloproteinases (MMP) are associated with the vascular remodelling seen in atherosclerosis and aneurysm. The activation and activity of MMP-2 are regulated by the intrinsic tissue inhibitor of MMP-2 (TIMP-2). The aim of the present study was to examine whether, conversely, MMP-2 can affect the gene and protein expression of TIMP-2. 2. In the present study, we examined the mRNA and protein expression of MMP-2 and TIMP-2 in cultured smooth muscle cells (SMC) from the aortas of MMP-2+/+ and MMP-2-/- mice. We also examined the roles of MMP-2 in SMC cellular events. 3. Western blotting showed that less TIMP-2 protein was present in the conditioned medium of MMP-2-/- SMC than in that of MMP-2+/+ SMC. Real-time reverse transcription polymerase chain reaction analysis showed that MMP-2 deficiency reduced TIMP-2 mRNA expression in SMC. Recombinant MMP-2 enhanced the expression of TIMP-2 protein in cultured SMC from MMP-2-/- mice. Furthermore, a siRNA targeting MMP-2 impaired the gene and protein expression of MMP-2 in cultured SMC from MMP-2+/+ mice. MMP-2 deficiency impaired SMC invasion, but not their proliferation, adhesion or migration. 4. Our findings suggest that MMP-2 is likely to be responsible, at least in part, for regulating TIMP-2 expression and is thus a potential target, in addition to TIMP-2, for therapeutics aimed at preventing cardiovascular remodelling in response to injury.