S-Methyl-L-cysteine targeting MsrA attenuates Ang II-induced oxidative stress and atrial remodeling via the p38 MAPK signaling pathway.

ABSTRACT

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). S-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. In vivo, SMLC (70, 140 and 280 mg kg-1 day-1) 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 in vitro 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.