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 (SC(1)) and TAC(1). Similarly, DKO mice (n = 20) were equally divided into two groups (i.e., SC(2) and ATC(2)). By days 28/60 after TAC, LV ejection fraction (LVEF) was significantly higher in TAC(2) than TAC(1), 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 TAC(1) and TAC(2) 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 TAC(1) and significantly higher in TAC(2) than those in the SC groups (P < 0.01). LV myocardial protein expressions of inflammation (TNF-alpha/NF-kappabeta), apoptosis (mitochondrial-Bax/cleaved caspase-3/PARP), oxidative stress (NOX-1/NOX-2/oxidized protein), fibrosis (Smad3/TGF-beta), DNA/mitochondrial damage (gamma-H2AX/cytosolic-cytochrome-C) and LV hypertrophy/pressure-overload (beta-MHC/BNP) biomarkers were significantly increased in TAC(2) compared to TAC(1) and SC groups, and significantly increased in TAC(1) 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.