Abstract Summary/Description
Background: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening vascular disease that remains challenging to manage and treat due to the lack of approved and effective pharmacotherapies. Growing reports show the therapeutic effects of ketone supplementation in several cardiovascular diseases. However, whether ketone supplementation can attenuate TAAD development is unknown. Methods: 3 weeks old C57BL/6J mice were given in drinking water either β-aminopropionitrile fumarate (BAPN) alone to induce TAAD or BAPN with ketone ester, a form of ketone supplementation. The BODIPY 581/591 C11 dye was used to assess lipid peroxidation in the cultured cells in vitro. Immunohistochemistry of the aorta was employed to detect ferroptotic markers. Mechanisms underlying ferroptotic regulation were studied using western blotting and qPCR. Results: Ketone ester supplementation lowered the incidence of TAAD and increased the survival rate in mice in vivo. Intriguingly, β-hydroxybutyrate (βHB), the most abundant form of ketone bodies, suppressed RSL-3 (Ras-selective lethal 3)-induced lipid peroxidation in human aortic smooth muscle cells (hASMCs). Furthermore, βHB elevated the protein levels of key ferroptosis regulators, including GPX4 (glutathione peroxidase 4) and SLC7A11 (solute carrier family 7 member 11) in hASMCs in vitro. Conclusions: This preliminary study uncovered an important and previously unrecognized role of ketone ester in ameliorating the pathogenesis of TAAD, which may be through GPX4 induction and subsequent ferroptosis inhibition in smooth muscle cells. Keywords: β-hydroxybutyrate; ferroptosis; thoracic aortic aneurysm; aortic dissection; aortic smooth muscle cells
