Autophagy Attenuates Vascular Calcification by Suppressing Ferroptosis

Background: Vascular calcification (VC) is an independent risk factor for cardiovascular death in chronic kidney disease. Autophagy is reported to be protective in VC, while the mechanism is not fully elucidated. Methods: RNA-sequencing and metabolomics of aortas from VD3-induced mice VC models (treated with or without Rapamycin) were used to identify potential signalings. RT-qPCR, Western blot (WB), and immunofluorescence staining were performed to confirm our findings, and gain-and-loss-of-function assays were conducted to validate the regulative mechanism of the involvement of ferroptosis in autophagy-mediated protective effect in VC. Results: We revealed that high phosphate could enhance the autophagy level of vascular smooth muscle cells (VSMCs), and autophagy plays a protective role in VC. Moreover, autophagy mainly occurred on the peroxisome of VSMCs in the high phosphate circumstances, which affects the level of ferroptosis. WB of ferroptosis markers GPX4 and TRF1 in high phosphate treated VSMCs confirmed this finding. Manipulating using ferroptosis inducer can reverse autophagy-mediated VC attenuation, while ferroptosis inhibition rescues Chloroquine induced elevated level of VC. Conclusions: Our results demonstrated that autophagy attenuates VC via preferable peroxisome inhibition, resulting in ferroptosis suppression. Funding: Government Support - Non-U.S.