Downregulation of HDAC9 by the ketone metabolite β‐hydroxybutyrate suppresses vascular calcification

• DOI: 10.1002/path.5992
• Publication Date: 2022-07-27T14:31:15Z
• Authors: Zirong Lan; An Chen; Li Li; Yuanzhi Ye; Qingchun Liang; Qianqian Dong; Siyi Wang; Mingwei Fu; Yining Li; Xiaoyu Liu; Zhenyu Zhu; Jing‐Song Ou; Xiaozhong Qiu; Lihe Lu; Jianyun Yan
• Keywords: 0303 health sciences; 3-Hydroxybutyric Acid; Myocytes, Smooth Muscle; NF-kappa B; Down-Regulation; Ketones; Histone Deacetylases; Muscle, Smooth, Vascular; Rats; 3. Good health; Repressor Proteins; Mice; 03 medical and health sciences; Animals; Humans; Calcium; Renal Insufficiency, Chronic; Vascular Calcification; Cells, Cultured

Abstract Vascular calcification is an actively regulated process resembling bone formation and contributes to the cardiovascular morbidity mortality of chronic kidney disease (CKD). However, effective therapy for vascular still lacking. The ketone body β‐hydroxybutyrate (BHB) has been demonstrated have health‐promoting effects including anti‐inflammation protective effects. whether BHB protects against in CKD remains unclear. In this study, Alizarin Red staining calcium content assay showed that reduced smooth muscle cells (VSMCs) arterial rings. Of note, compared with patients without thoracic calcification, serum levels were lower calcification. Supplementation 1,3‐butanediol (1,3‐B), precursor BHB, attenuated aortic rats VitD3‐overloaded mice. Furthermore, RNA‐seq analysis revealed downregulated HDAC9, which was further confirmed by RT‐qPCR western blot analysis. Both pharmacological inhibition knockdown HDAC9 human VSMCs, while overexpression exacerbated VSMCs rings, indicating promotes under conditions. treatment antagonized HDAC9‐induced addition, activated NF‐κB signaling pathway VSMC suggesting via activation NF‐κB. conclusion, our study demonstrates supplementation inhibits modulation HDAC9‐dependent pathway. Moreover, we unveil a crucial mechanistic role conditions; thus, nutritional intervention or approaches enhance could act as promising therapeutic strategies target CKD. © 2022 Pathological Society Great Britain Ireland.