Zha Yafang, Li Yanyan, Ge Zhuowang, Wang Jian, Jiao Yuheng, Zhang Jiayan, Zhang Song
Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Front Cardiovasc Med. 2022 Feb 10;9:797137. doi: 10.3389/fcvm.2022.797137. eCollection 2022.
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 injection aggravated cardiac fibrosis and impaired cardiac function in the myocardial infarction rat model. Furthermore, 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会导致心脏纤维化，这是心力衰竭的主要原因。据报道，含血小板反应蛋白基序的解聚素和金属蛋白酶8（ADAMTS8）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在心脏纤维化中的功能及其潜在机制。ADAMTS8在扩张型心肌病患者中的表达显著增加；在心肌梗死和主动脉缩窄（TAC）大鼠模型中其表达也增加，同时α-平滑肌肌动蛋白（α-SMA）和胶原蛋白1的表达也增加。通过心脏注射腺病毒介导的ADAMTS8过表达加重了心肌梗死大鼠模型的心脏纤维化并损害了心脏功能。此外，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，使心肌细胞和成纤维细胞能够间接通讯。我们的研究结果表明，ADAMTS8可损害心脏成纤维细胞的线粒体功能，进而激活磷脂酰肌醇-3激酶（PI3K）-蛋白激酶B（Akt）通路和丝裂原活化蛋白激酶（MAPK）通路，促进Yes相关蛋白（YAP）表达上调，该通路的上游是表皮生长因子受体（EGFR）。本研究系统地揭示了ADAMTS8在心脏纤维化中的促纤维化作用，并探讨了其作为治疗心脏纤维化和心力衰竭的治疗靶点的潜在作用。
