Endogenous Sulfur Dioxide Deficiency As a Driver of Cardiomyocyte Senescence Through Abolishing Sulphenylation of STAT3 at Cysteine 259

Objective: 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 2 ) 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 2 on cardiomyocyte senescence and the underlying molecular mechanisms. Approach and results: 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 2 content, elevated expression levels of Tp53, p21 Cip/Waf , and p16 INk4a , enhanced SA- beta -Gal activity, and elevated level of gamma -H2AX foci. Notably, supplementation with a SO 2 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 2 -induced STAT3 sulphenylation and subsequently prevented the inhibitory effect of SO 2 on STAT3-DNAbinding capacity, DNA damage, and cardiomyocyte senescence. Additionally, cardiomyocyte (cm) -specific AAT2 knockout (AAT2 cmKO ) mice exhibited a deterioration in cardiac function, cardiomegaly, and cardiac aging, whereas supplementation with SO 2 donors mitigated the cardiac aging and remodeling phenotypes in AAT2 cmKO mice. Conclusion: Downregulation of the endogenous SO 2 /AAT2 pathway is a crucial pathogenic mechanism underlying cardiomyocyte senescence. Endogenous SO 2 modifies STAT3 by sulphenylating Cys259, leading to the inhibition of DNA damage and the protection against cardiomyocyte senescence.