Abstract
The excessive intake of phosphate (Pi), or chronic kidney disease (CKD), can cause hyperphosphatemia and eventually lead to ectopic calcification, resulting in cerebrovascular diseases. It has been reported that reactive oxygen species (ROS), induced by high concentrations of Pi loading, play a key role in vascular calcification. Therefore, ROS suppression may be a useful treatment strategy for vascular calcification. 12AC3O is a newly synthesized gem-dihydroperoxide (DHP) that has potent antioxidant effects. In the present study, we investigated whether 12AC3O inhibited vascular calcification via its antioxidative capacity. To examine whether 12AC3O prevents vascular calcification under high Pi conditions, we performed Alizarin red and von Kossa staining, using the mouse aortic smooth muscle cell line p53LMAco1. Additionally, the effect of 12AC3O against oxidative stress, induced by high concentrations of Pi loading, was investigated using redox- sensitive dyes. Further, the direct trapping effect of 12AC3O on reactive oxygen species (ROS) was investigated by ESR analysis. Although high concentrations of Pi loading exacerbated vascular smooth muscle calcification, calcium deposition was suppressed by the treatment of both antioxidants and 12AC3O, suggesting that the suppression of ROS may be a candidate therapeutic approach for treating vascular calcification induced by high concentrations of Pi loading. Importantly, 12AC3O also attenuated oxidative stress. Furthermore, 12AC3O directly trapped superoxide anion and hydroxyl radical. These results suggest that ROS are closely involved in high concentrations of Pi-induced vascular calcification and that 12AC3O inhibits vascular calcification by directly trapping ROS.
Highlights
In recent years, the accelerating spread of processed foods and a Westernized diet have caused concerns regarding excessive phosphoric acid intake in Japan
High concentrations of Pi loading exacerbated vascular smooth muscle calcification, calcium deposition was suppressed by the treatment of both antioxidants and 12AC3O, suggesting that the suppression of reactive oxygen species (ROS) may be a candidate therapeutic approach for treating vascular calcification induced by high concentrations of Pi loading
12AC3O directly trapped superoxide anion and hydroxyl radical. These results suggest that ROS are closely involved in high concentrations of Pi-induced vascular calcification and that 12AC3O inhibits vascular calcification by directly trapping ROS
Summary
The accelerating spread of processed foods and a Westernized diet have caused concerns regarding excessive phosphoric acid intake in Japan. A method for generating new DHPs that can be adjusted from commercially available compounds was reported [36,37] Among these DHPs, 12AC3O leaded to apoptosis in K562 leukemia cells by scavenging intracellular ROS, without affecting the growth of peripheral blood monocytes (PBMCs) and fibroblasts [38]. We found that the DHP 12AC2O exerted a neuroprotective effect by inhibiting abnormal protein accumulation via the direct trapping of intracellular ROS in amyotrophic lateral sclerosis model cells [39]. We investigated the effect of 12aAcCt a3sORaOgSaisncasvt ehnighercsotnocrendturcaetiionntrsaoceflPlui-lainrdRuOcSeddacmalacgifiec. aIntiothneipnrVesSeMntCstsu. dy, we investigated the effect of 12AC3O against high concentrations of Pi‐induced calcification in VSMCs
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