Hydrogen sulfide attenuates oxidative stress-induced NLRP3 inflammasome activation via S-sulfhydrating c-Jun at Cys269 in macrophages.

Oxidative stress and inflammation are closely related to cardiovascular diseases. Although hydrogen sulfide (H2S) has been shown to have powerful anti-oxidative and anti-inflammatory properties, its role in macrophage inflammation was poorly understood. The aim of this study was to investigate the role of H2S in the regulation of macrophage NLRP3 inflammasome activation. We reported here that H2S attenuated hydrogen peroxide (H2O2)-induced NLRP3 inflammasome activation, which led to caspase-1 activation and IL-1ß production in macrophages. Moreover, H2S exerted its protective effects by lowering the generation of mitochondrial reactive oxygen species (mtROS). Mechanistically, S-sulfhydration of c-Jun by H2S enhanced its transcriptional activity on SIRT3 and p62, which contributed to the decrease of mtROS production. S-sulfhydration sites are investigated by site directed mutagenesis. Findings showed that S-sulfhydrated c-Jun exerted its protective influences via a c-Jun Cys269-dependent manner. Moreover, the protective effects of H2S were absent in macrophage from SIRT3 knockout mice. In conclusion, these results demonstrate that H2S attenuates oxidative stress-induced mtROS production and NLRP3 inflammasome activation via S-sulfhydrating c-Jun at cysteine 269 in macrophages.

Aliskiren protects against myocardial ischaemia-reperfusion injury via an endothelial nitric oxide synthase dependent manner.

Aliskiren, a direct renin inhibitor, has shown potent ability to attenuate hypertension. Our previous research has found that aliskiren protected against myocardial ischaemia-reperfusion (I/R) injury and enhanced phosphorylation of endothelial nitric oxide synthase (eNOS) in spontaneously hypertensive rats. However, whether the cardioprotective effect of aliskiren against myocardial I/R injury was eNOS-dependent is unknown. In the present study, 12-week-old male eNOS knockout (eNOS-/- ) and wild-type C57BL/6J mice (WT) were orally administrated with the dose of 50 mg/kg per day of aliskiren. After a 4-week treatment, aliskiren decreased blood pressure in eNOS-/- mice, and reduced renin-angiotension II levels in both eNOS-/- and WT mice. Aliskiren also improved left ventricular ejection fraction (EF) and fractional shortening (FS), decreased myocardial infarct size, reduced creatine kinase (CK) and lactate dehydrogenase (LDH) activity in plasma, attenuated dihydroethidium (DHE) fluorescence and levels of malondialdehyde (MDA), enhanced superoxide dismutase (SOD) activity and total antioxidant capacity (T-AOC) in myocardium, increased SOD and thioredoxin (Trx) proteins expression in WT mice subjected to 30 minutes of ischaemia followed by reperfusion for 24 hours. However, aliskiren failed to restore all of the above indices in eNOS-/- mice subjected to the same I/R injury. Our study indicated that aliskiren protected against myocardial I/R injury via an eNOS dependent manner.