β-Hydroxybutyrate Alleviates Atherosclerotic Calcification by Inhibiting Endoplasmic Reticulum Stress-Mediated Apoptosis via AMPK/Nrf2 Pathway

Background: Atherosclerotic calcification (AC) is a common feature of atherosclerotic cardiovascular disease. beta-Hydroxybutyrate (BHB) has been identified as a molecule that influences cardiovascular disease. However, whether BHB can influence AC is still unknown. Methods and Results: In this study, ApoE-/- mice, fed a Western diet, were used to examine the effects of BHB on AC. Rat vascular smooth muscle cells (VSMCs) were used to verify the impacts of BHB on AC and to explore the underlying mechanisms. The results show that Western diet-challenged ApoE-/- mice, supplemented with BHB for 24 weeks, exhibited reduced calcified areas, calcium content, and alkaline phosphatase (ALP) activity in the aortas, as well as ameliorated severity of AC. Furthermore, BHB downregulated the expression of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP), thereby reducing endoplasmic reticulum stress (ERS) and ERS-mediated apoptosis in the aortas of the mice. Consistently, in vitro studies showed that BHB reduced ALP activity and calcium content in VSMCs, and inhibited VSMC calcification. Additionally, BHB suppressed ERS-mediated apoptosis in VSMCs. Conclusions: In summary, the present results demonstrate that BHB can alleviate atherosclerotic calcification by inhibiting ERS-mediated apoptosis. Therefore, BHB may serve as a viable therapeutic agent for AC.