Sung Pei-Hsun, Chua Sarah, Chen Kuan-Hung, Sun Cheuk-Kwan, Li Yi-Chen, Huang Chi-Ruei, Luo Chi-Wen, Chai Han-Tan, Lu Hung-I, Yip Hon-Kan
Division of Cardiology, Department of Internl Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital Kaohsiung 83301, Taiwan.
Am J Transl Res. 2018 Sep 15;10(9):2781-2795. eCollection 2018.
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) and TAC. Similarly, DKO mice (n = 20) were equally divided into two groups (i.e., SC and ATC). By days 28/60 after TAC, LV ejection fraction (LVEF) was significantly higher in TAC than TAC, whereas LV end-systolic/diastolic dimensions displayed an opposite pattern to LVEF between the two groups (all < 0.05). By day 90, LVEF was significantly higher in SC groups than that in TAC and TAC 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 < 0.01). Total heart weight was highest in TAC and significantly higher in TAC than those in the SC groups ( < 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 TAC compared to TAC and SC groups, and significantly increased in TAC compared to SC groups (all < 0.001). Histopathology demonstrated that the fibrotic/collagen-deposition areas and sarcomere length exhibited an identical pattern to inflammation among the four groups (all < 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.
组织型纤溶酶原激活剂/基质金属蛋白酶-9[双敲除（DKO）]中的细胞外基质积累可能对小鼠横断主动脉缩窄（TAC）诱导的肥厚型心肌病后的左心室（LV）重塑和功能障碍具有保护作用。野生型C57BL/6小鼠（n = 20）被平均分为假手术对照组（SC）和TAC组。同样，DKO小鼠（n = 20）被平均分为两组（即SC和TAC）。在TAC后第28/60天，TAC组的左心室射血分数（LVEF）显著高于假手术对照组，而两组之间左心室收缩末期/舒张末期尺寸与LVEF呈现相反的模式（均P<0.05）。到第90天，SC组的LVEF显著高于TAC组和假手术对照组，后两组之间无显著差异，而所有组的左心室收缩末期/舒张末期尺寸、心肌细胞大小和右心室收缩压与LVEF呈现相反的模式（均P<0.01）。全心重量在TAC组最高，且TAC组显著高于SC组（P<0.01）。与假手术对照组和TAC组相比，TAC组左心室心肌中炎症（肿瘤坏死因子-α/核因子-κB）、凋亡（线粒体-促凋亡蛋白Bax/裂解的半胱天冬酶-3/聚（ADP-核糖）聚合酶）、氧化应激（NADPH氧化酶-1/NADPH氧化酶-2/氧化蛋白）、纤维化（Smad3/转化生长因子-β）、DNA/线粒体损伤（γ-H2AX/细胞溶质细胞色素C）和左心室肥厚/压力过载（β-肌球蛋白重链/脑钠肽）生物标志物的蛋白表达显著增加，与假手术对照组相比，TAC组也显著增加（均P<0.001）。组织病理学显示，四组中纤维化/胶原沉积区域和肌节长度与炎症呈现相同的模式（均P<0.0001）。总之，尽管在肥厚型心肌病的实验环境中，组织型纤溶酶原激活剂/基质金属蛋白酶-9似乎在早期可保留心脏功能，但它未能发挥长期保护作用。
