P221 DAPAGLIFLOZIN ASSOCIATED TO SACUBITRIL/VALSARTAN EXERTS ADDITIVE CARDIOPROTECTION IN HUMAN CARDIOMYOCYTES EXPOSED TO DOXORUBICIN AND TRASTUZUMAB THROUGH MYD88, NLRP3 MEDIATED PATHWAYS AND IMPROVEMENT OF MYTOGENESIS. (18th May 2022)

• Record Type: Journal Article
• Authors: Quagliariello, V; Iovine, M; Buccolo, S; Maurea, N
• Is Part Of: European heart journal supplements. Volume 24(2022)Supplement C
• Publication Date: 2022-05-18
• Subjects: Cardiology -- Periodicals; Cardiology -- Europe -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/suac012.213
• Languages: English
• ISSNs: 1520-765X

Abstract

Abstract: Introduction: The cumulative incidence of cardiac events in breast cancer patients treated with anthracycline and trastuzumab at 1 year after the diagnosis of cancer was 16.4%, at 2 years 23.8 %, and at 3 years 28.2%. Sodium glucose co–transporter 2 inhibitors showed measurable benefits in reduction of HF hospitalization and cardiovascular mortality. LCZ696 (neprilysin inhibitor + valsartan) as able to lower the risk of cardiovascular events in chronic heart failure. Purpose: We hypothesize that dapagliflozin associated to LCZ696 could exerts cardioprotective effects in cellular models of doxorubicin and trastuzumab–induced cardiotoxicity Methods: Human cardiomyocytes (HL–1 cells) were exposed to subclinical concentration of doxorubicin and trastuzumab (100 nM) alone or in combination with dapagliflozin (50 nM) or LCZ696 (at 100 mM) or both in combination for 48h. Cell viability, apoptosis and necrosis were performed. Quantification of MDA– 4–HNE and Ca2+ were performed through spectrophotometric methods. Anti–inflammatory studies were also performed (expression of NLRP3, TLR4/MyD88 pathways, nuclear expression of NF–kB). Intracellular concentration of IL–1α, IL–1β, IL–2, IL–4, IL–6, IL–8, IL–10, IL–12, IL17–α, IL–18, IFN–γ, TNF–α, G–CSF, and GM–CSF were also performed. Results: Dapagliflozin and LCZ696 increased synergistically the cell viability during exposure to doxorubicin and trastuzumab. Combination of dapagliflozin and LCZ696 reduces Ca2+ overload (–68, 4% vs cells treated only to anticancer drugs; p < 0, 001) and MDA (mean reduction of 57–63, 4 % compared to cells exposed only to anticancer drugs; p < 0, 05). The expression of MyD88, NLRP3 and NF–kB were strongly reduced after treatment with dapagliflozin and LCZ–696 (–52, 5, –43, 7 and –57, 3 % vs cells exposed only to anticancer drugs, respectively; p < 0.05). Notably, combination of dapagliflozin and LCZ–696 enhanced the expression of IL–10. Expression of IL–1α, IL–1β, IL–6, IL–8, IL17–α and IL–18 was reduced (p < 0.05). Mitogenesis was strictly improved also as demonstrated by confocal microscope analysis Conclusion: Dapagliflozin associated to LCZ–696 exerts additive cardioprotective and anti–inflammatory effects compared to each drug alone. Their properties are mediated by the reduction of iCa2+ content that consequently reduces peroxidation and NLRP3– MyD88 expression. These results indicating the potential use of SGLT–2 inhibitors associated to LCZ696 in preclinical models of cardiotoxicity.