Dapagliflozin as a sodium glucose cotransporter 2 inhibitor (SGLT2i) has been already developed as an effective hypoglycemic drug that target SGLT2 which is the main glucose transporter responsible for approximate 90% glucose reabsorption from primary urine in the kidney.1 Recently, lots of evidences have suggested Dapagliflozin effects on reducing body weight, glycosylated hemoglobin, plasma volume, blood pressure, increasing erythrocyte mass, and improving cardiac energy metabolism, which imposes many positive influences on the vast majority of cardiovascular risk factors and outcomes. 2,3,4 In view of the major clinical benefits of Dapagliflozin in improving cardiovascular outcomes, we propose a comprehensive and insightful theory of its pharmacological effects and underlying mechanisms in cardiovascular disease (CVD) prevention, which focus on addressing the mechanism of accelerating atherosclerosis associated with ferroptosis.
Ferroptosis is a nonapoptotic form of cell death regulated, which is induced by the over-production of phospholipid hydroperoxides in an iron-dependent manner.5–7 Dysregulation of ferroptosis is well known to associate with various pathological conditions and major diseases, such as atherosclerosis, ischemia-reperfusion, neurodegeneration and cancer. 8 Whereas, RSL3 is identified as a potent ferroptosis triggering agent, which depends on the activity of GPX4 (Shintoku et al., 2017). GPX4 to mediate suppression of ferroptosis (Friedmann Angeli et al., 2014; Yang et al., 2014).
Atherosclerosis is a main potential pathology of most CVDs, including acute myocardial infarction (AMI), heart failure (HF), stroke, and peripheral arterial disease. CVDs are generally acknowledged as the leading cause of morbidity and mortality globally.9 Atherosclerosis is a slow-progressing inflammatory process which includes a complex biochemical and cellular etiology characterized by the deposition of modified lipids in the arterial walls, the progress of lipid-laden atherosclerotic plaque and ultimate rupture of the plaque which precipitates a lethal clinical event being a heart attack or stroke.10 The clinically conventional risk factors for atherosclerosis and its complications include hypertension, overweight, smoking, dyslipidemia, depression, sedentary lifestyles and diabetes.11,12 In particularly, it has relationships between obesity, diabetes and dyslipidemia with dysregulation of ferroptosis. Patients with those conventional risk factors, especially those patients who already confirmed metabolic abnormalities have a higher risk of atherosclerosis and other complications associated with ferroptosis. 13–15
Normal cells require an adequate supply of nutrients and energy to survive and perform function. The deficiencies in nutrients and energy lead to a metabolic crisis. 16,17 One kind of metabolic crisis is called energy crisis, which is characterized by the deficiency of intracellular ATP. Initially, energy crisis leads to adaptive response, which induces reestablish energy homeostasis, however, under long-term and severe energy crisis with excessive deficiency of intracellular ATP, such adaptive responses cannot restore the energy balance and unresolved energy crisis eventually induces apoptosis. Whether the energy crisis regulates other nonapoptotic forms of cell death such as ferroptosis remains largely unknown.
In our study, we identified Dapagliflozin attenuated atherosclerosis by inhibiting ferroptosis of M2 macrophages through leading an energy crisis.18 So Dapagliflozin might be a potential new therapeutic medication target for atherosclerosis lesions in clinic.