Exogenous H2 S prevents the nuclear translocation of PDC-E1 and inhibits vascular smooth muscle cell proliferation in the diabetic state.

Hydrogen sulphide (H2 S) inhibits vascular smooth muscle cell (VSMC) proliferation induced by hyperglycaemia and hyperlipidaemia; however, the mechanisms are unclear. Here, we observed lower H2 S levels and higher expression of the proliferation-related proteins PCNA and cyclin D1 in db/db mouse aortae and vascular smooth muscle cells treated with 40 mmol/L glucose and 500 μmol/L palmitate, whereas exogenous H2 S decreased PCNA and cyclin D1 expression. The nuclear translocation of mitochondrial pyruvate dehydrogenase complex-E1 (PDC-E1) was significantly increased in VSMCs treated with high glucose and palmitate, and it increased the level of acetyl-CoA and histone acetylation (H3K9Ac). Exogenous H2 S inhibited PDC-E1 translocation from the mitochondria to the nucleus because PDC-E1 was modified by S-sulfhydration. In addition, PDC-E1 was mutated at Cys101. Overexpression of PDC-E1 mutated at Cys101 increased histone acetylation (H3K9Ac) and VSMC proliferation. Based on these findings, H2 S regulated PDC-E1 S-sulfhydration at Cys101 to prevent its translocation from the mitochondria to the nucleus and to inhibit VSMC proliferation under diabetic conditions.