心脏纤维化
血管紧张素II
纤维化
微泡
脂肪组织
外体
内分泌学
白色脂肪组织
内科学
肌成纤维细胞
心肌纤维化
脂肪细胞
医学
化学
小RNA
受体
生物化学
基因
作者
Mengqi Su,Wenpeng Li,Yue Yuan,Siyao Liu,Liang Chen,He Li,Ruixin Zhang,Yang Liu,Lei Sun,Wei Ying,Chunlei Li,Xuejie Han,Hongting Hao,Xinghui Zhao,Yingchun Luo,Sen Yan,Zhenwei Pan,Yue Li
标识
DOI:10.1016/j.trsl.2022.05.004
摘要
Cardiac fibrosis is a process characterized by extracellular matrix accumulation leading to myocardial dysfunction. Angiotensin II (Ang II) has been shown to play an important role in the pathogenesis of cardiac fibrosis. However, the underlying mechanisms are not well established. Dysfunction of adipose tissue has been shown to promote remote organ injury, but its role in Ang II-induced cardiac remodeling is still unclear. In this study, we demonstrated that epididymal white adipose tissue (eWAT) promoted Ang II-induced cardiac fibrosis and subsequent cardiac dysfunction in an exosome-dependent manner. Both eWAT removal and administration of an inhibitor of exosome biogenesis strongly attenuated Ang II-induced abnormalities. Moreover, exosomes isolated from Ang II-stimulated adipocytes promoted cardiac fibroblasts (CFs) activity. A mechanistic study identified that the miR-23a-3p level was significantly increased in exosomes derived from Ang II-challenged adipocytes and serum exosomes from Ang II-infused mice. Importantly, tail vein injection of ago-miR-23a-3p caused cardiac fibrosis and dysfunction, while antago-miR-23a-3p inhibited Ang II-induced cardiac fibrosis. Bioinformatics analysis and further validation experiments revealed that RAP1 is a direct downstream target of miR-23a-3p, and overexpression of RAP1 reversed the profibrotic effect of miR-23a-3p. Taken together, these findings elucidated the role of eWAT in Ang II-induced myocardial fibrosis and indicated that adipocyte-derived exosomes mediate pathologic communication between dysfunctional adipose tissue and the heart by transporting miR-23a-3p into CFs, transforming fibroblasts into myofibroblasts and promoting excessive collagen deposition by targeting RAP1. Prevention of abnormal adipocyte exosome production, inhibition of miR-23a-3p biogenesis, and treatment with a miR-23a-3p antagonist are novel strategies for treating cardiac fibrosis.
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