Sacubitril-valsartan activates pAMPK and reduces NLRP3, MyD88, cytokines/growth factors and DAMPs in doxorubicin-treated mice improving longitudinal strain and ejection fraction. (3rd October 2022)

• Record Type: Journal Article
• Authors: Maurea, N; Buccolo, S; Iovine, M; Paccone, A; Luciano, A; Barbieri, A; Palma, G; Maurea, C; Quagliariello, V
• Is Part Of: European heart journal. Volume 43(2022)Supplement 2
• Publication Date: 2022-10-03
• Subjects: Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehac544.2727
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Background: Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sacubitril-valsartan (LCZ 696) is a combination drug, made up of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan, used for the treatment of heart failure in patients with a reduced ejection fraction. Purpose: We hypothesized that LCZ 696, administered during doxorubicin, could improve cardiac function 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), LCZ-696 at 60 mg/kg (LCZ, n=6) or doxorubicin combined to LCZ-696 (DOXO-LCZ, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, DAMPs (galectine 3 and calgranulinS100), pAMPK, NF-kB, and 13 chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified through ELISA and western blot methods. Results: LCZ 696 improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88, DAMPs and NF-kB in cardiac tissues was seen in DOXO-LCZ group compared to DOXO mice (p<0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with LCZ-696 indicating anti-inflammatory properties. Expression of pAMPK was strongly enhanced in LCZ-696-DOXO compared to DOXO group. Levels of Calgranulin S100 and galectine-3 were strongly enhanced in DOXO group; on the other hand their expression were reduced by 47.7 and 52.3% in LCZ-696-DOXO group vs DOXO (p<0.005). Conclusion: In this preclinical study, LCZ-696 is able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis. The overall picture of the study pushes the use of Sacubitril-valsartan in prevention of cardiomyopathies induced by anthracyclines in cancer patients. Funding Acknowledgement: Type of funding sources: Public Institution(s). Main funding source(s): Ricerca Corrente, Ministero della Salute