Ge Mei, Zhang Lulu, Du Junbao, Jin Hongfang, Lv Boyang, Huang Yaqian
Department of Pediatrics, Children's Medical Center, Peking University First Hospital, Beijing, 100034, China.
State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China.
Heliyon. 2024 Jul 6;10(14):e34260. doi: 10.1016/j.heliyon.2024.e34260. eCollection 2024 Jul 30.
Endogenous sulfur dioxide (SO) plays a crucial role in protecting heart from myocardial fibrosis by inhibiting the excessive growth of cardiac fibroblasts. This study aimed to investigate potential mechanisms by which SO suppressed myocardial fibrosis.
Mouse model of angiotensin II (Ang II)-induced cardiac fibrosis and cell model of Ang II-stimulated cardiac fibroblast proliferation were employed. Our findings discovered that SO mitigated the aberrant phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) induced by Ang II, leading to a reduction of fibroblast proliferation. Mechanistically, for the first time, we found that SO sulfenylated ERK1/2, and inhibited ERK1/2 phosphorylation and cardiac fibroblast proliferation, while a sulfhydryl reducing agent dithiothreitol (DTT) reversed the above effects of SO. Furthermore, mutant ERK1 (cysteine 183 to serine) abolished the sulfenylation of ERK by SO, thereby preventing the inhibitory effects of SO on ERK1 phosphorylation and cardiac fibroblast proliferation.
Our study suggested that SO inhibited cardiac fibroblast proliferation by sulfenylating ERK1/2 and subsequently suppressing ERK1/2 phosphorylation. These new findings might enhance the understanding of the mechanisms underlying myocardial fibrosis and emphasize the potential of SO as a novel therapeutic target for myocardial fibrosis.
内源性二氧化硫（SO）通过抑制心脏成纤维细胞的过度生长，在保护心脏免受心肌纤维化方面发挥着关键作用。本研究旨在探讨SO抑制心肌纤维化的潜在机制。
采用血管紧张素II（Ang II）诱导的心脏纤维化小鼠模型和Ang II刺激的心脏成纤维细胞增殖细胞模型。我们的研究结果发现，SO减轻了Ang II诱导的细胞外信号调节激酶1/2（ERK1/2）的异常磷酸化，导致成纤维细胞增殖减少。机制上，我们首次发现SO使ERK1/2发生亚磺酰化，抑制ERK1/2磷酸化和成纤维细胞增殖，而巯基还原剂二硫苏糖醇（DTT）逆转了SO的上述作用。此外，突变型ERK1（半胱氨酸183突变为丝氨酸）消除了SO对ERK的亚磺酰化作用，从而阻止了SO对ERK1磷酸化和成纤维细胞增殖的抑制作用。
我们的研究表明，SO通过使ERK1/2发生亚磺酰化并随后抑制ERK1/2磷酸化来抑制心脏成纤维细胞增殖。这些新发现可能会加深对心肌纤维化潜在机制的理解，并强调SO作为心肌纤维化新治疗靶点的潜力。
