A disintegrin and metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis
A disintegrin and metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis
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DOI：
10.1152/ajpheart.00496.2019
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发表时间：
2020-02-01
影响因子：
4.8
通讯作者：
Shimomura, Iichiro
中科院分区：
文献类型：
--
作者：
Nakamura, Yuto;Kita, Shunbun;Shimomura, Iichiro
小分子 ADAM12 抑制剂 KB-R7785 通过抑制肝素结合 EGF 信号的蛋白水解激活来改善横主动脉缩窄 (TAC) 模型中的心脏功能，因此认为解整合素和金属蛋白酶 (ADAM)12 会促进心脏功能障碍。然而，该化合物对 ADAM12 的选择性较差，并且尚未使用遗传性功能丧失小鼠研究 ADAM12 在心功能障碍中的作用。我们发现，TAC 手术后 4 周，ADAM12 敲除小鼠比野生型小鼠表现出明显更严重的心脏肥大和更高的死亡率。 ADAM12 缺陷导致心脏纤维化显着扩大，同时衰竭心脏中胶原蛋白相关基因表达增加。全基因组转录分析的结果表明，ADAM12 敲除心脏中的粘着斑和纤维化相关信号通路显着增强。 ADAM12的缺失增加了整合素β1亚基和I型和III型转化生长因子(TGF)-β受体的丰度，随后心脏中粘着斑激酶、Akt、哺乳动物雷帕霉素靶点、ERK和Smad2/3磷酸化，导致心脏功能障碍。目前的结果表明，ADAM12 的缺失通过调节整合素 β 1 和 TGF-β 受体的丰度增强了粘着斑和典型的 TGF-β 信号传导。新的和值得注意的与长期认为的解整合素和金属蛋白酶 (ADAM)12 的心脏损伤作用相反，ADAM12 敲除小鼠的心脏肥大更严重，心功能更低，死亡率更高。主动脉缩窄手术。 ADAM12 的缺失增强了心脏中粘着斑和纤维化相关的信号通路，这可能会损害心脏功能。这些结果为开发针对 ADAM12 治疗心力衰竭的新型疗法提供了见解。
A disintegrin and metalloproteinase (ADAM)12 is considered to promote cardiac dysfunction based on the finding that a small-molecule ADAM12 inhibitor, KB-R7785, ameliorated cardiac function in a transverse aortic constriction (TAC) model by inhibiting the proteolytic activation of heparin-binding-EGF signaling. However, this compound has poor selectivity for ADAM12, and the role of ADAM12 in cardiac dysfunction has not yet been investigated using genetic loss-of-function mice. We revealed that ADAM12 knockout mice showed significantly more advanced cardiac hypertrophy and higher mortality rates than wild-type mice 4 wk after TAC surgery. An ADAM12 deficiency resulted in significantly more expanded cardiac fibrosis accompanied by increased collagen-related gene expression in failing hearts. The results of a genome-wide transcriptional analysis suggested a strongly enhanced focal adhesion- and fibrosis-related signaling pathway in ADAM12 knockout hearts. The loss of ADAM12 increased the abundance of the integrin beta 1 subunit and transforming growth factor (TGF)-beta receptor types I and III, and this was followed by the phosphorylation of focal adhesion kinase, Akt, mammalian target of rapamycin, ERK, and Smad2/3 in the heart, which resulted in cardiac dysfunction. The present results revealed that the loss of ADAM12 enhanced focal adhesion and canonical TGF-beta signaling by regulating the abundance of the integrin beta 1 and TGF-beta receptors.NEW & NOTEWORTHY In contrast to a long-believed cardio-damaging role of a disintegrin and metalloproteinase (ADAM)12, cardiac hypertrophy was more severe, cardiac function was lower, and mortality was higher in ADAM12 knockout mice than in wild-type mice after transverse aortic constriction surgery. The loss of ADAM12 enhanced focal adhesion- and fibrosis-related signaling pathways in the heart, which may compromise cardiac function. These results provide insights for the development of novel therapeutics that target ADAM12 to treat heart failure.