Dapagliflozin Attenuates Severity of Atherosclerosis through Manufacturing Energy-Crisis to Inhibit Ferroptosis of Macrophage

Abstract

Background: Atherosclerosis is a main potential pathology of most cardiovascular diseases. Growing evidence has indicated that dysregulation of ferroptosis is associated with atherosclerosis. Dapagliflozinas a sodiumglucose cotransporter 2 inhibitor (SGLT2i), in view of the clinically important benefits of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in improving cardiovascular outcomes, we aimed to explore its pharmacological effects and underlying mechanisms of atherosclerosis associated with ferroptosis. Method: Ferroptosis and severity of atherosclerosis were assessed in ApoE-/-(control) and ApoE-/-+Dapagliflozin (SGLT2i) mice groups to analyze the changes after Dapagliflozin treatment. ApoE-/-+Dapagliflozin+RSL3 (RSL3) mice group was established to confirm the association between ferroptosis and severity of atherosclerosis. Metabolism of nutrients and energetic phenotype of macrophages sorted by FACS within atherosclerosis plaques were analyzed to explore the mechanism of Dapagliflozin attenuating the severity of atherosclerosis. Result: Alleviated severity of atherosclerosis and ferroptosis were observed in Dapagliflozin treatment mice group, however, RSL3 treatment mice group revoke the beneficial effect. The metabolism of macrophages sorted by Fluorescence Activated Cell Sorter (FACS) with in atherosclerosis plaques indicated that Dapagliflozin treatment weakened fuel flexibility between mitochondrial respiration and nutrients consumption which leads to energy crisis within macrophages. The energy crisis mitigates ferroptosis and keeps more M2 macrophages surviving in atherosclerotic plaques. Conclusion: Dapagliflozin treatments modulate atherosclerotic plaque progression and maintain plaque stabilization by the way of creating energy crisis. Energy crisis keeps more M2 macrophages surviving in atherosclerotic plaque which is more sensitive to ferroptosis than M1 to attenuate severity of atherosclerosis. The pharmacological effects of Dapagliflozin might be a potential new therapeutic medication target for atherosclerosis lesions.