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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.

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.

American journal of translational research (2018-10-17)
Pei-Hsun Sung, Sarah Chua, Kuan-Hung Chen, Cheuk-Kwan Sun, Yi-Chen Li, Chi-Ruei Huang, Chi-Wen Luo, Han-Tan Chai, Hung-I Lu, Hon-Kan Yip
ABSTRACT

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.

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OxyBlot Protein Oxidation Detection Kit, The OxyBlot Protein Oxidation Detection Kit provides the reagents to perform the immunoblot detection of carbonyl groups introduced into proteins by oxidative reactions with ozone or oxides of nitrogen or by metal catalyzed oxidation.