Substitution of SERCA2 Cys674 aggravates cardiac fibrosis by promoting the transformation of cardiac fibroblasts to cardiac myofibroblasts
Substitution of SERCA2 Cys674 aggravates cardiac fibrosis by promoting the transformation of cardiac fibroblasts to cardiac myofibroblasts
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SERCA2 Cys674的替代通过促进心脏成纤维细胞向心肌成纤维细胞的转化而加重心脏纤维化
DOI：
10.1016/j.bcp.2022.115164
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Xiaoyong Tong
中科院分区：
文献类型：
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作者：
Xiaoyang Huang;Xiaojuan Lin;Langtao Wang;Yufei Xie;Yumei Que;Siqi Li;Pingping Hu;Xiaoyong Tong
肌浆/内质网Ca2+ atp酶2 （SERCA2）对维持细胞内钙稳态至关重要，其氧化还原Cys674（C674）是调节活性的关键。我们的目的是研究SERCA2 C674的氧化还原状态是否对心脏纤维化至关重要及其机制。杂合子SERCA2 C674S敲入（SKI）小鼠，其中一半的C674被丝氨酸取代，用于模拟病理条件下活性C674硫醇的部分损失。在心脏成纤维细胞中，C674巯基替代增加细胞质和线粒体内Ca2+水平及细胞内ROS水平，激活活化t淋巴细胞（NFAT）通路的钙调神经磷酸酶/核因子，增加促纤维化因子TGF-β1 （TGF-β1）、α平滑肌肌动蛋白、I型胶原和III型胶原的蛋白表达，促进心脏成纤维细胞向心肌成纤维细胞的转化，钙调神经磷酸酶/NFAT抑制剂可逆转这一过程。SERCA2激动剂，或ROS清除剂。激活SERCA2或清除ROS有利于缓解C674替代引起的心脏纤维化。综上所述，SERCA2中反应性C674巯基的部分缺失，通过激活钙调磷酸酶/NFAT/TGF-β1通路，促进心脏成纤维细胞向心肌成纤维细胞的转化，从而加剧了心脏纤维化，这凸显了C674氧化还原状态在维持心脏成纤维细胞稳态中的重要性。SERCA2是治疗心脏纤维化的潜在治疗靶点。
Sarcoplasmic/endoplasmic reticulum Ca2+ATPase 2 (SERCA2) is vital to maintain intracellular calcium homeostasis, and its redox Cys674(C674) is the key to regulating activity. Our goal was to investigate whether the redox state of SERCA2 C674 is critical for cardiac fibrosis and the mechanisms involved. Heterozygous SERCA2 C674S knock-in (SKI) mice, in which half of C674 was substituted by serine, were used to mimic the partial loss of the reactive C674 thiol in pathological conditions. In cardiac fibroblasts, the substitution of C674 thiol increased Ca2+levels in cytoplasm and mitochondria, and intracellular ROS levels, and activated calcineurin/nuclear factor of activated T-lymphocytes (NFAT) pathway, increased the protein expression of profibrotic factors TGF beta 1 (TGF-β1), alpha smooth muscle actin, collagen I and collagen III, and promoted the transformation of cardiac fibroblasts to cardiac myofibroblasts, which could be reversed by calcineurin/NFAT inhibitor, SERCA2 agonist, or ROS scavenger. Activation of SERCA2 or scavenging ROS is beneficial to alleviate cardiac fibrosis caused by the substitution of C674. In conclusion, the partial loss of the reactive C674 thiol in the SERCA2 exacerbates cardiac fibrosis by activating the calcineurin/NFAT/TGF-β1 pathway to promote the transformation of cardiac fibroblasts to cardiac myofibroblasts, which highlights the importance of C674 redox state in maintaining the homeostasis of cardiac fibroblasts. SERCA2 is a potential therapeutic target for the treatment of cardiac fibrosis.