Cardioprotective and anti-inflammatory effects of empagliflozin during treatment with doxorubicin: A cellular and preclinical study

Abstract

Background: Empagliflozin (EMPA), a selective inhibitor of the sodium glucose co-transporter 2, reduces the risk of hospitalization for heart failure or cardiovascular death, as seen in the EMPA-REG OUTCOME trial. Methods: We incubated EMPA alone or in combination with Doxorubicin in HL-1 adult cardiomyocytes evaluating: cell viability, lipid peroxidation, Leukotriene-B4 expression, NF-κB activation and Interleukin 1β, 8 and 6 secretion. To evaluate cardiac function in vivo, Global Longitudinal Strain (GLS) was measured using 2D speckle tracking echocardiography in C57BL6 mice treated with Doxorubicin (2.25 mg/kg/day ip) or EMPA (10 mg/kg/day) or EMPA and Doxorubicin in combination for 7 days. Cardiac lysates were processed for analysis of pro-inflammatory Interleukins. Results: EMPA, co-incubated with Doxorubicin, enhanced significantly the viability of cardiomyocytes, compared to only Doxorubicin treated cells. EMPA reduces the lipid peroxidation during exposure to Doxorubicin. Moreover, EMPA has shown anti-inflammatory activity reducing both Leukotriene B4 and NF-kB expression. Notably, EMPA also decreased the expression of IL-1β, IL-6 and IL-8 of 40-50 % for all, compared to only Doxorubicin exposed cells. In preclinical models, after treatments only with Doxorubicin, GLS decreased significantly, while associating the pretreatment and subsequent combinatorial treatment with EMPA, we observed a prevention of the GLS's reduction, indicating cardiprotective effects of the hypoglycemic drug. Moreover, we demonstrated that mice treated with EMPA and Doxorubicin the cardiac IL-1β, IL-6 and IL-8 were reduced of 45-60 % compared to mice treated only with Doxorubicin. Conclusions: We demonstrated for the first time that EMPA exerts anti-oxidant and anti-inflammatory properties during incubation with Doxorubicin. Preclinical studies demonstrated cardioprotective effects of EMPA, with significant reductions of key mediators of cardiotoxicity. These results lay the biochemical and pathophysiological bases for subsequent preclinical and clinical studies concerning the use of EMPA as a cardioprotective agent during treatment with Doxorubicin. Legal entity responsible for the study: The authors. Funding: “Ricerca Corrente” grant from the Italian Ministry of Health. Disclosure: All authors have declared no conflicts of interest.