Myocardial fibrosis is a characteristic of various cardiomyopathies, and myocardial fibroblasts play a central role in this process. Gelsolin (GSN) is an actin severing and capping protein that regulates actin assembly and may be involved in fibroblast activation. While the role of GSN in mechanical stress-mediated cardiac fibrosis has been explored, its role in myocardial fibrosis in the absence of mechanical stress is not defined. In this study, we investigated the role of GSN in myocardial fibrosis induced by Angiotensin II (Ang II), a profibrotic hormone that is elevated in cardiovascular disease. We utilized mice lacking GSN (Gsn^–/–) and cultured primary adult cardiac fibroblasts (cFB). In vivo, Ang II infusion in mice resulted in significantly less severe myocardial fibrosis in Gsn^–/– compared with Gsn^+/+ mice, along with diminished activation of the TGFβ1-Smad2/3 pathway, and reduced expression of cardiac extracellular matrix proteins (collagen, fibronectin, periostin). Moreover, Gsn-deficient hearts exhibited suppressed activity of the AMPK pathway and its downstream effectors, mTOR and P70S6Kinase, which could contribute to the suppressed TGFβ1 activity. In vitro, the Ang II-induced activation of cFBs was reduced in Gsn-deficient fibroblasts evident from decreased expression of αSMA and periostin, diminished actin filament turnover; which also exhibited reduced activity of the AMPK-mTOR pathway, and P70S6K phosphorylation. AMPK inhibition compensated for the loss of GSN, restored the levels of G-actin in Gsn^–/– cFBs and promoted activation to myofibroblasts by increasing αSMA and periostin levels. This study reveals a novel role for GSN in mediating myocardial fibrosis by regulating the AMPK-mTOR-P70S6K pathway in cFB activation independent from mechanical stress-induced factors.

中文翻译：

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凝溶胶蛋白是血管紧张素 II 诱导的心脏成纤维细胞活化和纤维化的重要介质

心肌纤维化是各种心肌病的特征，心肌成纤维细胞在这一过程中起核心作用。凝溶胶蛋白 (GSN) 是一种肌动蛋白切断和加帽蛋白，可调节肌动蛋白组装并可能参与成纤维细胞活化。虽然已经探索了 GSN 在机械应力介导的心脏纤维化中的作用，但它在没有机械应力的情况下在心肌纤维化中的作用尚未确定。在这项研究中，我们研究了 GSN 在血管紧张素 II (Ang II) 诱导的心肌纤维化中的作用，血管紧张素 II (Ang II) 是一种在心血管疾病中升高的促纤维化激素。我们利用缺乏 GSN ( Gsn ^–/– ) 的小鼠和培养的原代成年心脏成纤维细胞 (cFB)。在体内，注射 Ang II 可显着减轻小鼠心肌纤维化的严重程度Gsn ^–/–与Gsn ^+/+小鼠相比，TGFβ1-Smad2/3 通路的激活减弱，心脏细胞外基质蛋白（胶原蛋白、纤连蛋白、骨膜蛋白）表达降低。此外，Gsn 缺陷的心脏表现出 AMPK 通路及其下游效应器 mTOR 和 P70S6 激酶的抑制活性，这可能有助于抑制 TGFβ1 活性。在体外，Ang II 诱导的 cFBs 激活在Gsn中降低- αSMA 和骨膜蛋白表达减少，肌动蛋白丝周转减少，明显缺乏成纤维细胞；它还表现出 AMPK-mTOR 通路的活性降低和 P70S6K 磷酸化。AMPK 抑制补偿了 GSN 的损失，恢复了Gsn ^–/– cFB中 G-肌动蛋白的水平，并通过增加 αSMA 和骨膜蛋白水平促进了肌成纤维细胞的活化。这项研究揭示了 GSN 在介导心肌纤维化中的新作用，它通过调节 AMPK-mTOR-P70S6K 通路在 cFB 激活中独立于机械应力诱导因素。