Qiu Yufei, Song Xudong, Liu Yong, Wu Yan, Shi Jiayi, Zhang Fan, Pan Yu, Cao Zhiqin, Zhang Keke, Liu Jingruo, Chu Yanhui, Yuan Xiaohuan, Wu Dan
Heilongjiang Province Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, No.3, Tongxiang Street, Aimin District, Mudanjiang, 157011, Heilongjiang, China.
College of Life Sciences, Mudanjiang Medical University, Mudanjiang, 157011, Heilongjiang, China.
Appl Microbiol Biotechnol. 2023 Oct;107(20):6251-6262. doi: 10.1007/s00253-023-12722-x. Epub 2023 Aug 22.
Cardiac fibrosis is a remodeling process of the cardiac interstitium, characterized by abnormal metabolism of the extracellular matrix, excessive accumulation of collagen fibers, and scar tissue hyperplasia. Persistent activation and transdifferentiation into myofibroblasts of cardiac fibroblasts promote the progression of fibrosis. Transforming growth factor-β1 (TGF-β1) is a pivotal factor in cardiac fibrosis. Latency-associated peptide (LAP) is essential for activating TGF-β1 and its binding to the receptor. Thus, interference with TGF-β1 and the signaling pathways using LAP may attenuate cardiac fibrosis. Recombinant full-length and truncated LAP were previously constructed, expressed, and purified. Their effects on cardiac fibrosis were investigated in isoproterenol (ISO)-induced cardiac fibroblasts (CFs) and C57BL/6 mice. The study showed that LAP and tLAP inhibited ISO-induced CF activation, inflammation, and fibrosis, improved cardiac function, and alleviated myocardial injury in ISO-induced mice. LAP and tLAP alleviated the histopathological alterations and inhibited the elevated expression of inflammatory and fibrosis-related markers in cardiac tissue. In addition, LAP and tLAP decreased the ISO-induced elevated expression of TGF-β, αvβ3, αvβ5, p-Smad2, and p-Smad3. The study indicated that LAP and tLAP attenuated ISO-induced cardiac fibrosis via suppressing TGF-β/Smad pathway. This study may provide a potential approach to alleviate cardiac fibrosis. KEY POINTS: • LAP and tLAP inhibited ISO-induced CF activation, inflammation, and fibrosis. • LAP and tLAP improved cardiac function and alleviated myocardial injury, inflammation, and fibrosis in ISO-induced mice. • LAP and tLAP attenuated cardiac fibrosis via suppressing TGF-β/Smad pathway.
心脏纤维化是心脏间质的一种重塑过程，其特征为细胞外基质代谢异常、胶原纤维过度积聚以及瘢痕组织增生。心脏成纤维细胞的持续激活和向肌成纤维细胞的转分化促进了纤维化的进展。转化生长因子-β1（TGF-β1）是心脏纤维化中的关键因子。潜伏相关肽（LAP）对于激活TGF-β1及其与受体的结合至关重要。因此，利用LAP干扰TGF-β1及其信号通路可能会减轻心脏纤维化。先前已构建、表达并纯化了重组全长和截短型LAP。在异丙肾上腺素（ISO）诱导的心脏成纤维细胞（CFs）和C57BL/6小鼠中研究了它们对心脏纤维化的影响。研究表明，LAP和tLAP抑制了ISO诱导的CF激活、炎症和纤维化，改善了心脏功能，并减轻了ISO诱导小鼠的心肌损伤。LAP和tLAP减轻了组织病理学改变，并抑制了心脏组织中炎症和纤维化相关标志物的表达升高。此外，LAP和tLAP降低了ISO诱导的TGF-β、αvβ3、αvβ5、p-Smad2和p-Smad3的表达升高。该研究表明，LAP和tLAP通过抑制TGF-β/Smad通路减轻了ISO诱导的心脏纤维化。本研究可能为减轻心脏纤维化提供一种潜在方法。要点：• LAP和tLAP抑制了ISO诱导的CF激活、炎症和纤维化。• LAP和tLAP改善了心脏功能，并减轻了ISO诱导小鼠的心肌损伤、炎症和纤维化。• LAP和tLAP通过抑制TGF-β/Smad通路减轻了心脏纤维化。
