ADAMTSL3 knock-out mice develop cardiac dysfunction and dilatation with increased TGFβ signalling after pressure overload.
ADAMTSL3 knock-out mice develop cardiac dysfunction and dilatation with increased TGFβ signalling after pressure overload.
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DOI：
10.1038/s42003-022-04361-1
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发表时间：
2022-12-20
影响因子：
5.9
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中科院分区：
文献类型：
--
作者：
心力衰竭是世界范围内发病率和死亡率的主要原因，可由压力超负荷引起，心脏重构的特征是心肌细胞肥大和死亡、纤维化和炎症。在衰竭的心脏中，转化生长因子β促使心脏成纤维细胞向肌成纤维细胞分化，导致过度的细胞外基质产生和心脏重塑。需要新的策略来针对心力衰竭中的病理性转化生长因子β信号。在这里，我们展示了分泌的糖蛋白ADAMTSL3调节心脏中转化生长因子β。我们发现Adamtsl3基因敲除小鼠的心脏功能障碍和扩张加剧，死亡率增加，并且在主动脉缩窄的压力超负荷后，心脏表现出转化生长因子β活性和CFB激活。此外，在培养的CFB中过表达ADAMTSL3抑制转化生长因子β信号转导、肌成纤维细胞分化和胶原合成，提示ADAMTSL3通过调节转化生长因子β活性和CFB表型发挥心脏保护作用。这些结果为进一步研究ADAMTSL3在心力衰竭中的潜在有益作用奠定了基础。利用CRISPR-Cas9基因编辑技术，利用Adamtsl3基因缺陷小鼠研究了ADAMTSL3在心脏病理和心脏病中的作用。
Heart failure is a major cause of morbidity and mortality worldwide, and can result from pressure overload, where cardiac remodelling is characterized by cardiomyocyte hypertrophy and death, fibrosis, and inflammation. In failing hearts, transforming growth factor (TGF)β drives cardiac fibroblast (CFB) to myofibroblast differentiation causing excessive extracellular matrix production and cardiac remodelling. New strategies to target pathological TGFβ signalling in heart failure are needed. Here we show that the secreted glycoprotein ADAMTSL3 regulates TGFβ in the heart. We found that Adamtsl3 knock-out mice develop exacerbated cardiac dysfunction and dilatation with increased mortality, and hearts show increased TGFβ activity and CFB activation after pressure overload by aortic banding. Further, ADAMTSL3 overexpression in cultured CFBs inhibits TGFβ signalling, myofibroblast differentiation and collagen synthesis, suggesting a cardioprotective role for ADAMTSL3 by regulating TGFβ activity and CFB phenotype. These results warrant future investigation of the potential beneficial effects of ADAMTSL3 in heart failure. The role of ADAMTSL3 in heart pathology and cardiac disease is investigated with Adamtsl3-deficient mice using CRISPR-Cas9 gene editing.
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