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Role of double knockdown of tPA and MMP-9 on regulating the left ventricular function and remodeling followed by transverse aortic constriction-induced hypertrophic cardiomyopathy in mice.

This study tested the hypothesis that extracellular matrix accumulation in tPA-/-/MMP-9-/- [double-knockout (DKO)] may be protective against left ventricular (LV) remodeling and dysfunction following transverse aortic constriction (TAC)-induced hypertrophic cardiomyopathy in mice. Wild-type C57BL/6 mice (n = 20) were equally categorized into sham-control (SC1) and TAC1. Similarly, DKO mice (n = 20) were equally divided into two groups (i.e., SC2 and ATC2). By days 28/60 after TAC, LV ejection fraction (LVEF) was significantly higher in TAC2 than TAC1, whereas LV end-systolic/diastolic dimensions displayed an opposite pattern to LVEF between the two groups (all P < 0.05). By day 90, LVEF was significantly higher in SC groups than that in TAC1 and TAC2 without notable difference between the latter two groups, whereas LV end-systolic/diastolic dimensions, cardiomyocyte size and right-ventricular systolic pressure showed an opposite pattern compared with LVEF in all groups (all P < 0.01). Total heart weight was highest in TAC1 and significantly higher in TAC2 than those in the SC groups (P < 0.01). LV myocardial protein expressions of inflammation (TNF-α/NF-κβ), apoptosis (mitochondrial-Bax/cleaved caspase-3/PARP), oxidative stress (NOX-1/NOX-2/oxidized protein), fibrosis (Smad3/TGF-β), DNA/mitochondrial damage (γ-H2AX/cytosolic-cytochrome-C) and LV hypertrophy/pressure-overload (β-MHC/BNP) biomarkers were significantly increased in TAC2 compared to TAC1 and SC groups, and significantly increased in TAC1 compared to SC groups (all P < 0.001). Histopathology demonstrated that the fibrotic/collagen-deposition areas and sarcomere length exhibited an identical pattern to inflammation among the four groups (all P < 0.0001). In conclusion, although tPA-/-/MMP-9-/- seemed to preserve cardiac function in an experimental setting of hypertrophic cardiomyopathy at an early stage, it failed to exert long-term protective effect.