Abstract 4370545: β-Hydroxybutyrate Inhibits Thoracic Aortic Aneurysm and Dissection in Mice by Suppressing Ferroptosis

Abstract

Background: Thoracic aortic aneurysm and dissection (TAAD) is a severe vascular disease that poses life-threatening risks. Unfortunately, managing and treating TAAD remains challenging due to the absence of approved and effective pharmacological therapies. Recent studies have indicated that supplementation with the ketone body β-hydroxybutyrate (β-HB) may provide therapeutic benefits for various cardiovascular diseases. However, it is currently unknown whether β-HB supplementation can help reduce the development of TAAD. Methods: Three-week-old C57 BL/6J mice were fed β-aminopropionitrile fumarate (BAPN) to induce TAAD. Ketone ester, which produces β-HB, was administered in the drinking water of the TAAD mice. The C11-BODIPY581/591 dye was utilized to assess lipid peroxidation in cultured cells in vitro. Results: Ketone ester, a form of β-HB supplementation, reduced the incidence of BAPN-induced TAAD and increased survival rates in mice in vivo. Notably, β-HB, the most abundant type of ketone body, inhibited the lipid peroxidation induced by RSL-3 (Ras-selective lethal 3) in primary human aortic smooth muscle cells (hASMC). Additionally, β-HB increased the protein levels of key regulators of ferroptosis, including GPX4 (glutathione peroxidase 4) and SLC7A11 (solute carrier family 7 member 11), while decreasing the protein levels of heme oxygenase-1 (HO-1) in hASMC in vitro. HO-1 negatively regulated GPX4 protein levels. Furthermore, in vivo studies showed that ketone ester downregulated HO-1 and iron levels while increasing GPX4 expression in areas affected by TAAD. Conclusions: The preliminary study revealed a significant role of ketone ester in improving the pathogenesis of TAAD, likely through GPX4 induction and subsequent inhibition of ferroptosis in VSMC. Key Words: β-hydroxybutyrate; ferroptosis; thoracic aortic aneurysm; aortic dissection; HO-1; GPX4; aortic smooth muscle cells