Abstract 12601: Tissue Inhibitor of Matrix Metalloproteinase-4 Overexpression and Deletion- Effects on Survival and Collagen Accumulation with Pressure Overload Hypertrophy
Background: A structural milestone with LV pressure overload (PO) is myocardial collagen accumulation (COLL), alterations in determinants of COLL degradation, and increased levels of the tissue inhibitors of the matrix metalloproteinases (TIMPs). However, the mechanistic relationship between specific TIMPs, particularly TIMP-4 which is highly expressed in the LV, in the context of PO remains unknown. This study tested the hypothesis that myocardial selective overexpression (TIMP-4exp) or targeted deletion (TIMP-4KO) would directly alter the natural history and course of remodeling with PO.
Methods/Results: PO was induced in wild-type (WT; FVB n=25), TIMP-4exp (n=38; full length human TIMP-4), and TIMP-4KO (n=24) by transverse aortic constriction (TAC) and followed for 4 weeks. LV mass (LVM, echo; normalized to body weight, mg/g) and COLL (collagen volume fraction, CVF, %) were compared to WT-control (n=10). PO survival was higher in the TIMP-4exp and significantly worse in the TIMP-4KO (Figure). LVM increased with PO in all groups compared to WT control (WT: 4.7±0.1; TIMP-4KO: 5.4±0.3; TIMP-4exp: 4.2±0.1; vs WT-control: 2.9±0.1, all p<0.05) but was highest in TIMP-4KO (p<0.05 vs. WT and TIMP-4exp). COLL was increased with PO in all groups (WT: 1.6±0.1; TIMP-4KO: 1.8±0.2; TIMP-4exp: 1.4±0.1; vs WT-control: 0.6±0.1, all p<0.05). With PO, COLL was lower in the TIMP-4exp group compared to WT and TIMP4-KO (both p<0.05).
Conclusions: These unique results demonstrated modulating a specific TIMP, TIMP-4 which is increased in patients with PO, directly alters survival, compensatory growth response and matrix remodeling.
- © 2010 by American Heart Association, Inc.