Orally administered chondroitin sulfate oligosaccharides attenuate hypertension via multiple protective pathways, including Hmox1-mediated antioxidant responses.

Abstract

Chondroitin sulfate (CS) is a sulfated glycosaminoglycan with various physiological functions. We previously prepared a mixture of chondroitin sulfate oligosaccharides (CSOS) derived from skate cartilage and evaluated its absorption in humans using urinary CS excretion as an indicator. The results suggested that CSOS is absorbed more efficiently than intact high-molecular-weight CS (HMwCS). However, the plasma pharmacokinetics and biological effects of CSOS after administration remained unclear. The present study aimed to clarify these aspects. Pharmacokinetic analysis based on plasma exogenous CS concentrations revealed that CSOS was absorbed, whereas no absorption of HMwCS was observed. Consistent with this finding, a Caco-2 cell assay using CS with different molecular weights showed that lower-molecular-weight CS had greater permeability. To investigate the biological potential of absorbed CSOS, we evaluated its antihypertensive activity in spontaneously hypertensive rats (SHR/Kpo) and explored the underlying mechanisms using microarray analysis. CSOS administration for 12 weeks significantly attenuated hypertension in SHR/Kpo rats. Microarray analysis revealed altered gene expression in analyzed tissues. Among them, we focused on the upregulation of heme oxygenase-1 (Hmox1) in arterial vessels and blood, which has been implicated in oxidative stress-related blood pressure regulation. To evaluate the effect of CSOS on HMOX1 expression, its constituent CS oligomers were examined in EAhy.926 endothelial cells. CS disaccharide (CS2-mer) induced HMOX1 expression, consistent with transcription factor activation. Comparison of CS2-mer analogs indicated that the C6-sulfated disaccharide induced HMOX1 expression without cytotoxicity. These findings suggest that CSOS attenuates hypertension partly through vascular HMOX1 induction, possibly involving the C6-sulfated disaccharide.