Reduced Production of Hydrogen Sulfide and Sulfane Sulfur Due to Low Cystathionine β-Synthase Levels in Brain Astrocytes of Stroke-Prone Spontaneously Hypertensive Rats.

Stroke-prone spontaneously hypertensive rats (SHRSP/Izm; SHRSP) develop severe hypertension and die of cerebral stroke. However, the genetic mechanisms underlying their stroke susceptibility have not been clarified yet. In this study, we used astrocytes from the newborn brain cortex of spontaneously hypertensive rats (SHR/Izm; SHR) and SHRSP to find the difference of genetic characteristics. Astrocytes are known to have functions of vasodilation and nutrient uptake for neurons in the brain. The continuous generation of hydrogen peroxide (H2O2) dose-dependently causes cell death in astrocytes, and SHRSP was more vulnerable than SHR. We found that the total thiols decreased in SHRSP astrocytes but the total glutathione (GSH) did not change. Hydrogen sulfide (H2S), which is known to protect cells through anti-oxidant and vasodilatory effects, is produced by cystathionine β-synthase (CBS) in astrocytes. We found that H2S production was significantly decreased in SHRSP as compared to SHR. This was caused by the decreasing expression of mRNA, protein and enzyme activity of CBS in astrocytes. We also found that astrocyte cell death from oxidative stress could be prevented by GYY4137 H2S donor. H2S is also known to cause protein S-sulfhydration to modify enzyme activity. Sulfane sulfur in astrocytes was significantly lower in SHRSP and decreased by CBS inhibitor. We showed that astrocytes in SHRSP vulnerable to oxidative stress may be caused by reduction of H2S through lower expression and activity of CBS.