Data_Sheet_4_ADAMTS8 Promotes Cardiac Fibrosis Partly Through Activating EGFR Dependent Pathway.ZIP

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.

心肌梗死或压力超负荷可引发心纤维化，该现象是导致心力衰竭的首要原因。据研究报道，ADAMTS8（一种具有血栓素样基序的金属蛋白酶和丝氨酸蛋白酶8）与多种纤维化相关疾病的发生密切相关。然而，ADAMTS8在由心肌梗死或压力超负荷引起的心纤维化中的具体作用尚未明了。本研究旨在探讨ADAMTS8在心纤维化中的作用及其潜在机制。在扩张型心肌病患者中，ADAMTS8的表达显著升高；在心肌梗死和TAC大鼠模型中，其表达亦有所增加，伴随α-SMA和胶原蛋白1表达的上调。通过心脏原位注射腺病毒介导的ADAMTS8过表达加剧了心肌梗死大鼠模型的心纤维化，并损害了心脏功能。此外，体外研究揭示了ADAMTS8可促进心脏成纤维细胞的活化；ADAMTS8作为一种旁分泌介质，允许心肌细胞和成纤维细胞间接进行交流。我们的研究结果揭示了ADAMTS8对心脏成纤维细胞线粒体功能的损伤，进而激活PI3K-Akt和MAPK信号通路，促进YAP表达的上调，其中EGFR位于该通路的上游。本研究系统地揭示了ADAMTS8在心纤维化中的促纤维化效应，并探讨了其作为治疗心纤维化和心力衰竭潜在治疗靶点的可能性。