Liang Jianwen, Huang Jieping, He Wanbing, Shi Guangzi, Chen Jie, Huang Hui
Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong, China.
Department of Cardiology, the Eighth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.
Front Cardiovasc Med. 2021 Aug 20;8:685748. doi: 10.3389/fcvm.2021.685748. eCollection 2021.
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. 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 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. 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. 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 autophagy enhancement.
血管钙化（VC）是衰老的一个标志，而热量限制诱导产生的β-羟基丁酸（BHB）已被确定为延长寿命的一个有前景的因素。然而，BHB对VC的影响及其潜在机制仍不清楚。共有160名有或没有代谢异常（MA）的受试者根据不同的钙化严重程度被分为四组。通过中介分析研究了BHB、MA和VC之间的关联。然后，利用高磷诱导的钙化模型，研究了BHB对动脉环钙化和血管平滑肌细胞（VSMC）成骨表型分化的影响。此后，检测了自噬生物标志物的表达、自噬通量以及自噬抑制剂对VC的影响。在老年人中观察到严重的VC，同时伴有较高比例的高血压、慢性肾脏病以及较低的估计肾小球滤过率。血清BHB水平是VC严重程度的一个独立影响因素。通过中介分析，BHB被确定为MA对VC影响中的一个重要中介，且BHB的间接效应占总效应的23%。此外，BHB直接抑制动脉环钙化和VSMC的成骨表型分化，同时伴有VSMC自噬增强。相应地，自噬的抑制抵消了BHB对VC的保护作用。本研究表明，BHB介导了MA对VC的影响；然后，进一步阐明BHB可通过增强自噬来抑制动脉和VSMC钙化。
