Abstract

Streptolysin O (SLO) is produced by common hemolytic streptococci that cause a wide range of diseases from pharyngitis to life-threatening necrotizing fasciitis and toxic shock syndrome. While the importance of SLO in invasive hemolytic streptococcus infection has been well demonstrated, the role of circulating SLO in non-invasive infection remains unclear. The aim of this study was to characterize the pharmacological effect of SLO on vascular functions, focusing on cellular signaling pathways. In control Wistar rats, SLO treatment (1-1000 ng/mL) impaired acetylcholine-induced endothelial-dependent relaxation in the aorta and second-order mesenteric artery in a dose-dependent manner, without any effects on sodium nitroprusside-induced endothelium-independent relaxation or agonist-induced contractions. SLO also increased phosphorylation of the endothelial NO synthase (eNOS) inhibitory site at Thr495 in the aorta. Pharmacological analysis indicated that either endothelial dysfunction or eNOS phosphorylation was mediated by protein kinase Cβ (PKCβ), but not by the p38 mitogen-activated protein kinase (MAPK) pathway. Consistent with this, SLO increased phosphorylation levels of PKC substrates in the aorta. In vivo study of control Wistar rats indicated that intravenous administration of SLO did not change basal blood pressure, but significantly counteracted the acetylcholine-induced decrease in blood pressure. Interestingly, plasma anti-SLO IgG levels were significantly higher in 10- to 15-week-old spontaneously hypertensive rats compared to age-matched control rats (P<0.05). These findings demonstrated that SLO causes vascular endothelial dysfunction, which is mediated by PKCβ-induced phosphorylation of the eNOS inhibitory site.

Significance Statement This study showed for the first time, that in vitro exposure of vascular tissues to SLO impairs endothelial function, an effect that is mediated by PKCb-induced phosphorylation of the eNOS inhibitory site. Intravenous administration of SLO in control and hypertensive rats blunted the ACh-induced decrease in blood pressure, providing evidence for a possible role of SLO in dysregulation of blood pressure.