State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theatre Command, Shenyang 110016, China.
Postgraduate College, Shenyang Pharmaceutical University, Shenyang 110016, China.
Food Funct. 2024 Sep 16;15(18):9165-9175. doi: 10.1039/d4fo03078h.
Atrial fibrillation (AF) is the most prevalent sustained tachyarrhythmia in patients with cardiovascular diseases. Recently, it has been discovered that oxidative stress is an important contributor to AF. Therefore, antioxidant therapies for AF have great potential for clinical applications. Methionine, a sulfur-containing amino acid residue other than cysteine, is recognized as a functional redox switch, which could be rescued from the reversible oxidation of methionine sulfoxide by methionine sulfoxide reductase A (MsrA). -Methyl-L-cysteine (SMLC), a natural analogue of Met, which is abundantly found in garlic and cabbage, could substitute for Met oxidations and mediate MsrA to scavenge free radicals. However, whether SMLC alleviates AF is unclear. This study aims to clarify the effects of SMLC on AF and elucidate the underlying pharmacological and molecular mechanisms. , SMLC (70, 140 and 280 mg kg day) was orally administered to mice for 4 weeks with angiotensin II (Ang II) by subcutaneous infusion using osmotic pumps to induce AF. Ang II significantly prompted high AF susceptibility and atrial remodeling characterized by oxidative stress, conductive dysfunction and fibrosis. SMLC played a remarkable protective role in Ang II-induced atrial remodeling dose-dependently. Moreover, RNA sequencing was performed on atrial tissues to identify the differentially expressed mRNA, which was to screen out MSRA, CAMK2 and MAPK signaling pathways. Western blots confirmed that Ang II-induced downregulation of MsrA and upregulation of oxidized CaMKII (ox-CaMKII) and p38 MAPK could be reversed in a concentration-dependent manner by SMLC. To investigate the underlying mechanisms, HL-1 cells (mouse atria-derived cardiomyocytes) treated with Ang II were used for an model. SMLC alleviated Ang II-induced cytotoxicity, mitochondrial damage and oxidative stress. Additionally, knockdown MsrA could attenuate the protective effects of SMLC, which were eliminated by the p38 MAPK inhibitor SB203580. In summary, the present study demonstrates that SMLC protects against atrial remodeling in AF by inhibiting oxidative stress through the mediation of the MsrA/p38 MAPK signaling pathway.
心房颤动（AF）是心血管疾病患者中最常见的持续性快速性心律失常。最近，人们发现氧化应激是 AF 的一个重要诱因。因此，抗氧化治疗在 AF 中有很大的临床应用潜力。甲硫氨酸（Met）是一种含硫氨基酸残基，除半胱氨酸外，它被认为是一种功能性氧化还原开关，可通过甲硫氨酸亚砜还原酶 A（MsrA）从甲硫氨酸亚砜的可逆氧化中得到恢复。-甲基-L-半胱氨酸（SMLC）是 Met 的天然类似物，大量存在于大蒜和卷心菜中，可替代 Met 氧化，并介导 MsrA 清除自由基。然而，SMLC 是否能缓解 AF 尚不清楚。本研究旨在阐明 SMLC 对 AF 的影响，并阐明其潜在的药理和分子机制。, SMLC（70、140 和 280 mg kg 天）通过皮下输注血管紧张素 II（Ang II）用渗透泵口服给予小鼠 4 周，以诱导 AF。Ang II 显著促进了高 AF 易感性和心房重构，表现为氧化应激、传导功能障碍和纤维化。SMLC 对 Ang II 诱导的心房重构具有显著的保护作用，呈剂量依赖性。此外，对心房组织进行 RNA 测序以鉴定差异表达的 mRNA，以筛选出 MSRA、CAMK2 和 MAPK 信号通路。Western blot 证实，Ang II 诱导的 MsrA 下调和氧化型钙调蛋白激酶 II（ox-CaMKII）和 p38 MAPK 的上调可被 SMLC 浓度依赖性地逆转。为了研究其潜在机制，用 Ang II 处理 HL-1 细胞（小鼠心房来源的心肌细胞）建立模型。SMLC 减轻了 Ang II 诱导的细胞毒性、线粒体损伤和氧化应激。此外，敲低 MsrA 可减弱 SMLC 的保护作用，而 p38 MAPK 抑制剂 SB203580 可消除这种作用。总之，本研究表明，SMLC 通过介导 MsrA/p38 MAPK 信号通路抑制氧化应激来保护 AF 中的心房重构。
