β-Hydroxybutyric Inhibits Vascular Calcification via Autophagy Enhancement in Models Induced by High Phosphate

Jianwen Liang; Jieping Huang; Wanbing He; Guangzi Shi; Jie Chen; Hui Huang

doi:10.3389/fcvm.2021.685748

β-Hydroxybutyric Inhibits Vascular Calcification via Autophagy Enhancement in Models Induced by High Phosphate

Front Cardiovasc Med. 2021 Aug 20:8:685748. doi: 10.3389/fcvm.2021.685748. eCollection 2021.

Authors

Jianwen Liang^{1

2}, Jieping Huang¹, Wanbing He¹, Guangzi Shi³, Jie Chen⁴, Hui Huang^{1

2}

Affiliations

¹ Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong, China.
² Department of Cardiology, the Eighth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.
³ Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangdong, China.
⁴ Department of Radiation Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong, China.

Abstract

Background: Vascular calcification (VC) is a landmark of aging, while β-hydroxybutyric acid (BHB) induced by calorie restriction has been identified as a promising factor to extend the lifespan. However, the effect of BHB on VC and the potential mechanism remain unknown. Methods: A total of 160 subjects with or without metabolic abnormalities (MAs) were assigned to four groups according to different calcification severities. The association between BHB, MAs, and VC was investigated via mediation analysis. Then, with high phosphate-induced calcification models, the effect of BHB on arterial ring calcification and osteogenic phenotypic differentiation of vascular smooth muscle cells (VSMCs) was investigated. Hereafter the expressions of autophagy biomarkers, autophagy flux, and effects of autophagy inhibitors on VC were detected. Results: Severe VC was observed in the elderly, accompanied with a higher proportion of hypertension, chronic kidney disease, and lower estimated glomerular filtration rate. The serum BHB level was an independent influencing factor of VC severities. With mediation analysis, BHB was determined as a significant mediator in the effects of MAs on VC, and the indirect effect of BHB accounted for 23% of the total effect. Furthermore, BHB directly inhibited arterial ring calcification and osteogenic phenotypic differentiation in VSMCs, accompanied with autophagy enhancement in VSMCs. In accordance, the inhibition of autophagy counteracted the protective effect of BHB on VC. Conclusion: The present study demonstrated that BHB mediated the effects of MAs on VC; then, it further elucidated that BHB could inhibit arterial and VSMC calcification via autophagy enhancement.

Keywords: metabolic abnormalities; osteogenic phenotypic differentiation; vascular calcification; vascular smooth muscle cells; β-hydroxybutyric acid.