ADAMTS8 Promotes Cardiac Fibrosis Partly Through Activating EGFR Dependent Pathway.
ADAMTS8 Promotes Cardiac Fibrosis Partly Through Activating EGFR Dependent Pathway.
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DOI：
10.3389/fcvm.2022.797137
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发表时间：
2022
影响因子：
3.6
通讯作者：
Zhang S
中科院分区：
文献类型：
--
作者：
Zha Y;Li Y;Ge Z;Wang J;Jiao Y;Zhang J;Zhang S
心肌梗死或压力超负荷会导致心脏纤维化，这是心力衰竭的主要原因。ADAMTS8(带有血栓反应蛋白基序的去整合素和金属蛋白酶8)已被报道与许多纤维化相关疾病有关。然而，ADAMTS8在心肌梗死或压力超负荷引起的心脏纤维化中的具体作用尚不清楚。本研究旨在探讨ADAMTS8在心肌纤维化中的作用及其机制。ADAMTS8在扩张型心肌病患者中的表达显著增加；其在心肌梗死和大鼠心肌梗死模型中的表达也明显增加，并伴有α-SMA和胶原蛋白1的表达增加。腺病毒介导的ADAMTS8心脏原位注射过表达可加重心肌梗死大鼠模型的心肌纤维化和心功能损害。此外，体外研究表明，ADAMTS8促进心脏成纤维细胞的激活；ADAMTS8作为旁分泌介质，允许心肌细胞和成纤维细胞间接通信。我们的研究结果表明，ADAMTS8可以损伤心脏成纤维细胞的线粒体功能，进而激活PI3K-Akt通路和MAPK通路，促进YAP表达上调，EGFR位于该通路的上游。本研究系统地揭示了ADAMTS8在心脏纤维化中的促纤维化作用，并探索其作为治疗心脏纤维化和心力衰竭的潜在靶点的作用。
Myocardial infarction or pressure overload leads to cardiac fibrosis, the leading cause of heart failure. ADAMTS8 (A disintegrin and metalloproteinase with thrombospondin motifs 8) has been reported to be involved in many fibrosis-related diseases. However, the specific role of ADAMTS8 in cardiac fibrosis caused by myocardial infarction or pressure overload is yet unclear. The present study aimed to explore the function of ADAMTS8 in cardiac fibrosis and its underlying mechanism. ADAMTS8 expression was significantly increased in patients with dilated cardiomyopathy; its expression myocardial infarction and TAC rat models was also increased, accompanied by increased expression of α-SMA and Collagen1. Adenovirus-mediated overexpression of ADAMTS8 through cardiac in situ injection aggravated cardiac fibrosis and impaired cardiac function in the myocardial infarction rat model. Furthermore, in vitro studies revealed that ADAMTS8 promoted the activation of cardiac fibroblasts; ADAMTS8 acted as a paracrine mediator allowing for cardiomyocytes and fibroblasts to communicate indirectly. Our findings showed that ADAMTS8 could damage the mitochondrial function of cardiac fibroblasts and then activate the PI3K-Akt pathway and MAPK pathways, promoting up-regulation of YAP expression, with EGFR upstream of this pathway. This study systematically revealed the pro-fibrosis effect of ADAMTS8 in cardiac fibrosis and explored its potential role as a therapeutic target for the treatment of cardiac fibrosis and heart failure.