DOI: 10.1161/circ.148.suppl_1.15043 ISSN: 0009-7322

Abstract 15043: Dapagliflozin Reduces Systemic NLRP-3, IL-1 and PCSK9 Levels in Preclinical Models of Short-Term Doxorubicin Cardiotoxicity: New Evidences of SGLT2i Use in Cardioncology

Nicola Maurea, Maria Laura Canale, Irma Bisceglia, Giuseppe Palma, Antonio Luciano, Francesca Bruzzese, Martina Iovine, Alessia Merola, Andrea Paccone, Domenico Gabrielli, Fabrizio Maurea, Vincenzo Quagliariello
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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.

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