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,BIOCHEMICAL PHARMACOLOGY

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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
BIOCHEMICAL PHARMACOLOGY ( IF 5.3 ) Pub Date : 2022-07-06 , DOI: 10.1016/j.bcp.2022.115164
Xiaoyang Huang ₁ , Xiaojuan Lin ₁ , Langtao Wang ₁ , Yufei Xie ₁ , Yumei Que ₁ , Siqi Li ₁ , Pingping Hu ₁ , Xiaoyong Tong ₁

Affiliation

肌浆/内质网Ca ATP酶2（SERCA2）对于维持细胞内钙稳态至关重要，其氧化还原Cys（C674）是调节活性的关键。我们的目标是研究 SERCA2 C674 的氧化还原状态是否对心脏纤维化及其相关机制至关重要。杂合 SERCA2 C674S 敲入 (SKI) 小鼠（其中一半 C674 被丝氨酸取代）用于模拟病理条件下反应性 C674 硫醇的部分丢失。在心脏成纤维细胞中，C674硫醇的取代增加了细胞质和线粒体中的Ca水平以及细胞内ROS水平，并激活了钙调磷酸酶/活化T淋巴细胞核因子（NFAT）途径，增加了促纤维化因子TGFβ1（TGF）的蛋白表达-β1)、α平滑肌肌动蛋白、I型胶原和 III型胶原，并促进心脏成纤维细胞向心肌成纤维细胞的转化，这种转化可以被钙调神经磷酸酶/NFAT抑制剂、SERCA2激动剂或ROS清除剂逆转。激活SERCA2或清除ROS有利于减轻C674替代引起的心脏纤维化。总之，SERCA2中反应性C674硫醇的部分丢失通过激活钙调神经磷酸酶/NFAT/TGF-β1通路促进心脏成纤维细胞向心肌成纤维细胞转化而加剧心脏纤维化，这凸显了C674氧化还原状态在维持心肌成纤维细胞中的重要性。心脏成纤维细胞的稳态。 SERCA2是治疗心脏纤维化的潜在治疗靶点。

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Substitution of SERCA2 Cys674 aggravates cardiac fibrosis by promoting the transformation of cardiac fibroblasts to cardiac myofibroblasts

Sarcoplasmic/endoplasmic reticulum Ca ATPase 2 (SERCA2) is vital to maintain intracellular calcium homeostasis, and its redox Cys (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 Ca 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.

更新日期：2022-07-06

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