Baker Heart and Diabetes Institute , Melbourne, Victoria , Australia.
Central Clinical School, Monash University , Melbourne, Victoria , Australia.
Am J Physiol Heart Circ Physiol. 2018 Jun 1;314(6):H1169-H1178. doi: 10.1152/ajpheart.00337.2017. Epub 2018 Feb 9.
Preclinical studies have demonstrated that anti-galectin-3 (Gal-3) interventions are effective in attenuating cardiac remodeling, fibrosis, and dysfunction. We determined, in a transgenic (TG) mouse model of fibrotic cardiomyopathy, whether Gal-3 expression was elevated and whether Gal-3 played a critical role in disease development. We studied mice with fibrotic cardiomyopathy attributable to cardiac overexpression of human β-adrenoceptors (β-TG). Cardiac expression levels of Gal-3 and fibrotic or inflammatory genes were determined. The effect of Gal-3 inhibition in β-TG mice was studied by treatment with Gal-3 inhibitors ( N-acetyllactosamine and modified citrus pectin) or by deletion of Gal-3 through crossing β-TG and Gal-3 knockout mice. Changes in cardiomyopathy phenotypes were assessed by echocardiography and biochemical assays. In β-TG mice at 3, 6, and 9 mo of age, upregulation of Gal-3 expression was observed at mRNA (6- to 15-fold) and protein (4- to 8-fold) levels. Treatment of β-TG mice with N-acetyllactosamine (3 wk) or modified citrus pectin (3 mo) did not reverse cardiac fibrosis, inflammation, and cardiomyopathy. Similarly, Gal-3 gene deletion in β-TG mice aged 3 and 9 mo did not rescue the cardiomyopathy phenotype. In conclusion, the β-TG model of cardiomyopathy showed a robust upregulation of Gal-3 that correlated with disease severity, but Gal-3 inhibitors or Gal-3 gene deletion had no effect in halting myocardial fibrosis, remodeling, and dysfunction. Gal-3 may not be critical for cardiac fibrogenesis and remodeling in this cardiomyopathy model. NEW & NOTEWORTHY We showed a robust upregulation of cardiac galectin-3 (Gal-3) expression in a mouse model of cardiomyopathy attributable to cardiomyocyte-restricted transgenic activation of β-adrenoceptors. However, pharmacological and genetic inhibition of Gal-3 did not confer benefit in this model, implying that Gal-3 may not be a critical disease mediator of cardiac remodeling in this model.
临床前研究表明，抗半乳糖凝集素-3（Gal-3）干预可有效减轻心脏重构、纤维化和功能障碍。我们在纤维化性心肌病的转基因（TG）小鼠模型中确定，Gal-3 表达是否升高，以及 Gal-3 是否在疾病发展中起关键作用。我们研究了归因于心脏过表达人β-肾上腺素能受体（β-TG）的纤维化性心肌病的小鼠。确定 Gal-3 和纤维化或炎症基因的心脏表达水平。通过用 Gal-3 抑制剂（N-乙酰乳糖胺和改性柑橘果胶）或通过将β-TG 和 Gal-3 基因敲除小鼠杂交来敲除 Gal-3，研究 Gal-3 抑制在β-TG 小鼠中的作用。通过超声心动图和生化测定评估心肌病表型的变化。在 3、6 和 9 月龄的β-TG 小鼠中，Gal-3 表达的上调在 mRNA（6-15 倍）和蛋白（4-8 倍）水平上均可见。用 N-乙酰乳糖胺（3 周）或改性柑橘果胶（3 个月）治疗β-TG 小鼠并未逆转心脏纤维化、炎症和心肌病。同样，在 3 和 9 月龄的β-TG 小鼠中敲除 Gal-3 基因也不能挽救心肌病表型。总之，β-TG 心肌病模型显示 Gal-3 的强烈上调与疾病严重程度相关，但 Gal-3 抑制剂或 Gal-3 基因缺失对阻止心肌纤维化、重构和功能障碍没有影响。Gal-3 可能不是该心肌病模型中心脏纤维化和重构的关键因素。
我们在一种归因于心肌细胞特异性转基因激活β-肾上腺素能受体的心肌病小鼠模型中观察到心脏半乳糖凝集素-3（Gal-3）表达的强烈上调。然而，Gal-3 的药理学和基因抑制在该模型中没有带来益处，这表明 Gal-3 可能不是该模型中心脏重构的关键疾病介质。
