Cardiomyocyte senescence is an important contributor to cardiovascular diseases and can be induced by stressors including DNA damage, oxidative stress, mitochondrial dysfunction, epigenetic regulation, etc. However, the underlying mechanisms for the development of cardiomyocyte senescence remain largely unknown. Sulfur dioxide (SO) is produced endogenously by aspartate aminotransferase 2 (AAT2) catalysis and plays an important regulatory role in the development of cardiovascular diseases. The present study aimed to explore the effect of endogenous SO on cardiomyocyte senescence and the underlying molecular mechanisms. We interestingly found a substantial reduction in the expression of AAT2 in the heart of aged mice in comparison to young mice. AAT2-knockdowned cardiomyocytes exhibited reduced SO content, elevated expression levels of Tp53, p21, and p16, enhanced SA-β-Gal activity, and elevated level of γ-H2AX foci. Notably, supplementation with a SO donor ameliorated the spontaneous senescence phenotype and DNA damage caused by AAT2 deficiency in cardiomyocytes. Mechanistically, AAT2 deficiency suppressed the sulphenylation of signal transducer and activator of transcription 3 (STAT3) facilitated its nuclear translocation and DNA-binding capacity. Conversely, a mutation in the cysteine (Cys) 259 residue of STAT3 blocked SO-induced STAT3 sulphenylation and subsequently prevented the inhibitory effect of SO on STAT3-DNA-binding capacity, DNA damage, and cardiomyocyte senescence. Additionally, cardiomyocyte (cm)-specific AAT2 knockout (AAT2) mice exhibited a deterioration in cardiac function, cardiomegaly, and cardiac aging, whereas supplementation with SO donors mitigated the cardiac aging and remodeling phenotypes in AAT2 mice. Downregulation of the endogenous SO/AAT2 pathway is a crucial pathogenic mechanism underlying cardiomyocyte senescence. Endogenous SO modifies STAT3 by sulphenylating Cys259, leading to the inhibition of DNA damage and the protection against cardiomyocyte senescence.

中文翻译：

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内源性二氧化硫缺乏通过消除 STAT3 半胱氨酸 259 的磺化作用来驱动心肌细胞衰老

心肌细胞衰老是心血管疾病的重要诱因，可由DNA损伤、氧化应激、线粒体功能障碍、表观遗传调控等应激源引起。然而，心肌细胞衰老发生的潜在机制仍不清楚。二氧化硫（SO）是由天冬氨酸转氨酶2（AAT2）催化内源性产生的，在心血管疾病的发生发展中发挥着重要的调节作用。本研究旨在探讨内源性SO对心肌细胞衰老的影响及其分子机制。有趣的是，我们发现与年轻小鼠相比，老年小鼠心脏中 AAT2 的表达显着减少。 AAT2 敲低的心肌细胞表现出 SO 含量降低、Tp53、p21 和 p16 表达水平升高、SA-β-Gal 活性增强以及 γ-H2AX 灶水平升高。值得注意的是，补充 SO 供体可改善心肌细胞中 AAT2 缺陷引起的自发衰老表型和 DNA 损伤。从机制上讲，AAT2 缺陷抑制了信号转导子和转录激活子 3 (STAT3) 的磺化，促进了其核转位和 DNA 结合能力。相反，STAT3 的半胱氨酸 (Cys) 259 残基的突变阻止了 SO 诱导的 STAT3 磺化，并随后阻止了 SO 对 STAT3-DNA 结合能力、DNA 损伤和心肌细胞衰老的抑制作用。此外，心肌细胞（cm）特异性AAT2敲除（AAT2）小鼠表现出心脏功能恶化、心脏肥大和心脏老化，而补充SO供体可减轻AAT2小鼠的心脏老化和重塑表型。内源性 SO/AAT2 通路的下调是心肌细胞衰老的重要致病机制。内源性 SO 通过磺化 Cys259 来修饰 STAT3，从而抑制 DNA 损伤并防止心肌细胞衰老。