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

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.

Serum biomarkers for arterial calcification in humans: A systematic review

“…Thirty-four articles published results investigating a possible association between calcium and arterial calcification ( Alagoz et al, 2014 ; Arad et al, 1998 ; Billington et al, 2020 ; Chen et al, 2006 ; Criqui et al, 2010 ; Foley et al, 2009 ; Grønhøj et al, 2016 ; Kim et al, 2013 ; Kwak et al, 2014 ; Liang et al, 2021 ; Nam et al, 2017 ; Nielsen et al, 2021 ; Park et al, 2011 ; Park et al, 2016 ; Shin et al, 2012 ; Tuersun et al, 2020 ; Tuttle and Short, 2009 ; Wei et al, 2020 ; Wu et al, 2016b ; Zagura et al, 2011 ; Barbarash et al, 2016 ; Cancela et al, 2012 ; Chai et al, 2017 ; Davaine et al, 2016 ; Diederichsen et al, 2017 ; Donate-Correa et al, 2019 ; Golovkin et al, 2016 ; Liu et al, 2019 ; Masai et al, 2013 ; Pirro et al, 2013 ; Schlieper et al, 2010 ; Torii et al, 2016 ; Awan et al, 2010 ; Razavi et al, 2021 ). Of these studies, nine reported positive associations ( Grønhøj et al, 2016 ; Kwak et al, 2014 ; Nielsen et al, 2021 ; Shin et al, 2012 ; Tuttle and Short, 2009 ; Zagura et al, 2011 ; Diederichsen et al, 2017 ; Golovkin et al, 2016 ; Awan et al, 2010 ) and 25 reported no significant association ( Alagoz et al, 2014 ; Arad et al, 1998 ; Billington et al, 2020 ; Chen et al, 2006 ; Criqui et al, 2010 ; Foley et al, 2009 ; Kim et al, 2013 ; Liang et al, 2021 ...…”

“…Thirty-five studies investigated a possible association between phosphate and arterial calcification ( Alagoz et al, 2014 ; Billington et al, 2020 ; Chen et al, 2006 ; Criqui et al, 2010 ; Foley et al, 2009 ; Grønhøj et al, 2016 ; Kim et al, 2013 ; Kwak et al, 2014 ; Liang et al, 2021 ; Nam et al, 2017 ; Nielsen et al, 2021 ; Park et al, 2011 ; Park et al, 2016 ; Shin et al, 2012 ; Tuersun et al, 2020 ; Tuttle and Short, 2009 ; Wei et al, 2020 ; Wu et al, 2016b ; Barbarash et al, 2016 ; Cancela et al, 2012 ; Chai et al, 2017 ; Diederichsen et al, 2017 ; Donate-Correa et al, 2019 ; Golovkin et al, 2016 ; Liu et al, 2019 ; Masai et al, 2013 ; Pirro et al, 2013 ; Schlieper et al, 2010 ; Torii et al, 2016 ; Awan et al, 2010 ; Razavi et al, 2021 ; Martín-Reys et al, 2016 ; Barbarash et al, 2019 ; McPherson et al, 2012 ; Park et al, 2020 ). Of these studies, fourteen reported a significant positive association ( Foley et al, 2009 ; Kim et al, 2013 ; Kwak et al, 2014 ; Park et al, 2011 ; Park et al, 2016 ; Shin et al, 2012 ; Tuersun et al, 2020 ; Tuttle and Short, 2009 ; Cancela et al, 2012 ; Diederichsen et al, 2017 ; Barbarash et al, 2019 ; McPherson et al, 2012 ; Park et al, 2020 ), three a negative association ( Chen et al, 2006 ; Kim et al, 2013 ; Razavi et al, 2021 ...…”

Molecular mechanisms and effects of urocortin II on rat adventitial fibroblast calcification induced by calcified medium

“…As an adaptive response to cellular stress, autophagy is critical in maintaining vascular structure and function. Previous studies have shown increased levels of autophagy during vascular calci cation [20,21]. Autophagy can inhibit vascular calci cation through a variety of mechanisms.…”

Exercise Ameliorates Atherosclerosis via Up-Regulating Serum β-Hydroxybutyrate Levels

“…In vitro, after OxLDL treatment of PMs for 6 h, LC3II increased, indicating that autophagy was activated to promote the clearance of lipids, but 12 h later, LC3II expression decreased and the protein level of P62 continued to rise, meaning that autophagy was dysfunctional in the PMs. It has been reported that the stimulation of BHB activates the associated autophagic signaling pathway and inhibits vascular calcification via enhanced autophagy [ 60 ]. In addition, BHB also can upregulate FOXO1 to activate autophagy in the liver [ 26 ].…”