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Updated: Aug 8, 2025
Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation
Published on: May 31, 2016
VX-765 ameliorates CKD VSMC calcification by regulating STAT3 activation
Yingjie Duan1, Zhong Peng2, Shuzhu Zhong1
1The First Affiliated Hospital, Department of Nephrology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
Background:
Recent clinical evidences show that caspase-1 inhibitor-VX-765 attenuates atherosclerosis in ApoE deficient mice. However, there is rarely information about the effect of VX-765 on hyperphosphatemia-induced vascular smooth muscle cells (VSMCs) calcification or vascular calcification in chronic kidney disease (CKD) rats. Here we investigate the effect of VX-765 on vascular calcification in uremia circumstances.
Methods:
Hyperphosphatemia-induced VSMC calcification were evaluated by Alizarin Red S. Aortas from CKD rats which were gavaged with VX-765 were examined for calcification signal using micro-CT. Levels of NLRP3, caspase-1, and GSDMD were measured by quantitative real-time PCR, western blotting, immunofluorescence assay, and immunohistochemistry.
Results:
We demonstrated for the first time that the levels of NLRP3, caspase-1, GSDMD, IL-1β, and IL-18 were up-regulated in hyperphosphatemia-induced calcifying VSMCs. Blockade of caspase-1 activation by VX-765 inhibited pyroptosis-related molecules and VSMC calcification in a concentration-dependent manner in vitro. Further analysis of aortas from calcified CKD rats showed an up-regulation of caspase-1 and GSDMD expression compared with those non-calcified vascular tissue from control rats or with those decreased-calcified vascular tissue from CKD rats treated with 50 mg/kg/d, which indicated that pyroptotic indicators were tightly correlated with CKD arterial calcification. In vitro studies further demonstrated that VX-765 ameliorated hyperphosphatemia-induced VSMCs calcification through inhibiting the STAT3 activation.
Conclusions:
Our findings indicated that VX-765 could inhibit hyperphosphatemia-induced calcifying VSMCs and ameliorate vascular calcification in CKD rats. VX-765 might be a potential treatment strategy for CKD vascular calcification.
Insights
The caspase-1 inhibitor VX-765 reduces vascular calcification in chronic kidney disease (CKD) rats by inhibiting pyroptosis. This study suggests VX-765 as a potential treatment for vascular calcification in CKD patients.
Area of Science:
- Cardiovascular Research
- Nephrology
- Molecular Biology
Background:
- Vascular calcification is a complication of chronic kidney disease (CKD).
- Caspase-1 inhibitor VX-765 shows promise in atherosclerosis, but its effect on CKD-related vascular calcification is unknown.
- This study investigates VX-765's impact on hyperphosphatemia-induced vascular calcification in CKD.
Purpose of the Study:
- To evaluate the effect of VX-765 on vascular smooth muscle cell (VSMC) calcification in hyperphosphatemia.
- To assess VX-765's efficacy in preventing vascular calcification in a rat model of CKD.
- To elucidate the molecular mechanisms underlying VX-765's action.
Main Methods:
- VSMC calcification assessed using Alizarin Red S staining.
- Aortic calcification in CKD rats evaluated via micro-CT scanning.
- Expression of NLRP3, caspase-1, and GSDMD measured by qPCR, western blotting, and immunohistochemistry.
Main Results:
- NLRP3, caspase-1, GSDMD, IL-1β, and IL-18 were upregulated in hyperphosphatemia-induced VSMCs.
- VX-765 inhibited VSMC calcification and pyroptosis-related molecules in vitro.
- VX-765 treatment reduced vascular calcification in CKD rats and inhibited STAT3 activation.
Conclusions:
- VX-765 effectively inhibits hyperphosphatemia-induced VSMC calcification and ameliorates vascular calcification in CKD rats.
- The findings suggest VX-765 as a potential therapeutic strategy for CKD-associated vascular calcification.
- Caspase-1 and pyroptosis are key players in CKD vascular calcification.
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