細菌毒素streptolysin Oが血管内皮に及ぼす影響：ディスバイオシスと高血圧症との関連

抄録

Emerging evidences provide a microbial imbalance (dysbiosis) is linked to several diseases including cardiovascular diseases. It has been reported that Gram-positive Streptococcus genus is increased in feces of spontaneous hypertensive rat (SHR) with increased intestinal permeability. However, the mechanism by which the dysbiosis induces increased blood pressure remains unknown. We hypothesized that bacterial toxin derived from gut Streptococcus genus in hypertension may cause dysregulation of blood pressure. In this study, we examined the effect of streptolysin O, a streptococcal pyrogenic exotoxin, on vascular function using Wistar rat. Treatment with streptolysin O (10-1000 ng/ml, 30 min) did not change contractile responses to phenylephrine or serotonin in aorta (n=4). In contrast, streptolysin O significantly impaired acetylcholine-induced endothelial dependent relaxation in a dose-dependent manner (n=6, p<0.05), while sodium nitroprusside-induced endothelial independent relaxation was unchanged (n=4). Streptolysin O increased the level of eNOS phosphorylation at Thr495 (n=6). Endothelial dysfunction caused by streptolysin O was attenuated by pan protein kinase C (PKC) inhibitor (Ro 31-8222, n=6, p<0.05), PKCβ inhibitor (LY 333531, n=5, p<0.05) or selective PKCβ2 inhibitor (GCP53353, n=3, p<0.05). We conclude that streptolysin O may cause increment of blood pressure through vascular endothelial dysfunction, which is mediated by PKCβ2-induced phosphorylation of eNOS inhibitory site.