SGLT2i Dapagliflozin decreases NLRP3, IL-1 and PCSK9 expression in preclinical models of short-term doxorubicin cardiotoxicity

Abstract Background Anthracyclines are an effective and widely used chemotherapy agent in the treatment of multiple solid organ tumors and hematologic malignancies. The use of anthracyclines as a standard cancer therapy is limited by the potential for the development of cardiac dysfunction, arrhythmias, and clinical heart failure. In recent five years, it was demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9), a lipid metabolism-related protein, is a key orchestrator of immune infiltration in myocardial and cancer tissues and could regulate cardiac fibrosis and inflammation. PCSK9 is a protein with key roles in hepatic low density lipoprotein (LDL) homeostasis. PCSK9 systemic levels are associated to HOMA score and high insulin levels. Dapagliflozin exerts systemic ant-inflammatory properties and cardioprotective effects in diabetic and non-diabetic patients. Purpose We hypothesized that Dapagliflozin, administered during doxorubicin, could reduce PCSK9 systemic levels in preclinical models. Methods Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO-DAPA, n=6). After treatments, plasma levels of PCSK9, IL-1β and CRP were analyzed through selective anti-mouse ELISA methods. Myocardial and liver expression of NLRP3-inflammasome and IL-1β were analyzed through ELISA method in tissue lysates after treatments. Results DAPA associated to DOXO reduces significantly systemic levels of PCSK9 ( -37,5% vs DOXO group, p<0,001). IL-1β and CRP levels were also reduced ( -47,3 and – 28,5 %, respectively; p<0.05 for both). Myocardial and liver IL-1β and NLRP3 inflammasome expression were also reduced in DAPA/DOXO group vs DOXO and control, indicated beneficial metabolic and anti-inflammatory effects of SGLT2i. Conclusion DAPA has been shown to reduce systemic levels of PCSK9 in preclinical models of short-term DOXO cardiotoxicity. To the best of our knowledge, this is the first evidence of SGLT-2/PCSK9 crass-talk in cardioncology therefore the overall picture of the study open a new window on the beneficial properties of DAPA against anthracyclines side effects.