Background:Myocardial Gal3 (galectin-3) expression is associated with cardiac inflammation and fibrosis. Increased Gal3 portends susceptibility to heart failure and death. There are no data reporting the causative role of Gal3 to mediate cardiac fibro-inflammatory response and heart failure.Methods:We developed a cardioselective Gal3 gain-of-function mouse (Gal3+/+) using α-myosin heavy chain promotor. We confirmed Gal3-transgene expression with real-time polymerase chain reaction and quantified cardiac/circulating Gal3 with Western blot and immunoassays. We used echocardiogram and cardiac magnetic resonance imaging to measure cardiac volumes, function, and myocardial velocities. Ex vivo, we studied myocardial inflammation/fibrosis and downstream TGF (transforming growth factor) β1-mRNA expression. We examined the effects of acute myocardial ischemia in presence of excess Gal3 by inducing acute myocardial infarction in mice. Two subsets of mice including mice treated with N-acetyl-seryl-aspartyl-lysyl-proline (a Gal3-inhibitor) and mice with genetic Gal3 loss-of-function (Gal3−/−) were studied for comparative analysis of Gal3 function.Results:Gal3+/+ mice had increased cardiac/circulating Gal3. Gal3+/+ mice showed excess pericardial fat pad, dilated ventricles and cardiac dysfunction, which was partly normalized by N-acetyl-seryl-aspartyl-lysyl-proline. Cardiac magnetic resonance imaging showed reduced myocardial contractile velocities in Gal3+/+. The majority of Gal3+/+ mice did not survive acute myocardial infarction, and the survivors had profound cardiac dysfunction. Myocardial histology of Gal3+/+ mice showed macrophage/mast-cell infiltration, fibrosis and higher TGFβ1-mRNA expression, which were mitigated by both Gal3 gene deletion and N-acetyl-seryl-aspartyl-lysyl-proline administration.Conclusions:Our study shows that cardioselective Gal3 overexpression leads to multiple cardiac phenotypic defects including ventricular dilation and cardiac dysfunction. Pharmacological Gal3 inhibition conferred protective effects with reduction of inflammation and fibrosis. Our study highlights the importance of translational studies to counteract Gal3 function and prevent cardiac dysfunction.

中文翻译：

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小内源性肽减轻心脏选择性 Galectin-3 过表达小鼠模型中的心肌重塑

背景：心肌Gal3（galectin-3）表达与心脏炎症和纤维化有关。Gal3 增加预示着对心力衰竭和死亡的易感性。没有数据报告 Gal3 介导心脏纤维炎症反应和心力衰竭的致病作用。方法：我们开发了心脏选择性 Gal3 功能获得小鼠（Gal3+/+) 使用 α-肌球蛋白重链启动子。我们通过实时聚合酶链反应确认了 Gal3 转基因表达，并通过蛋白质印迹和免疫测定对心脏/循环 Gal3 进行了量化。我们使用超声心动图和心脏磁共振成像来测量心脏容量、功能和心肌速度。离体，我们研究了心肌炎症/纤维化和下游 TGF（转化生长因子）β1-mRNA 表达。我们通过在小鼠中诱导急性心肌梗死来检查在过量 Gal3 存在下急性心肌缺血的影响。研究了两组小鼠，包括用 N-乙酰-丝氨酰-天冬氨酰-赖氨酰-脯氨酸（一种 Gal3 抑制剂）治疗的小鼠和具有遗传性 Gal3 功能丧失（Gal3 -/-）的小鼠，以比较分析 Gal3 功能。结果：Gal3+/+小鼠心脏/循环Gal3增加。Gal3+/+小鼠表现出过多的心包脂肪垫、扩张的心室和心功能不全，这部分被 N-乙酰-丝氨酰-天冬氨酰-赖氨酰-脯氨酸恢复正常。心脏磁共振成像显示Gal3+/+ 中心肌收缩速度降低。大多数Gal3+/+小鼠未能在急性心肌梗塞中存活，幸存者有严重的心功能不全。Gal3+/+的心肌组织学小鼠表现出巨噬细胞/肥大细胞浸润、纤维化和更高的 TGFβ1-mRNA 表达，这些均因 Gal3 基因缺失和 N-乙酰-丝氨酰-天冬氨酰-赖氨酰-脯氨酸给药而减轻。结论：我们的研究表明，心脏选择性 Gal3 过表达导致多种心脏表型缺陷，包括心室扩张和心功能不全。药理学 Gal3 抑制作用具有减少炎症和纤维化的保护作用。我们的研究强调了转化研究对抵消 Gal3 功能和预防心功能不全的重要性。