Empaglifozin has cardioprotective and anti-inflammatory effects during doxorubicin treatment: A preclinical study.

Abstract

e23057 Background: Empagliflozin (EMPA), a selective inhibitor of the sodium glucose co-transporter 2 (SGLT2), reduces the risk of hospitalization for heart failure or cardiovascular death in type 2 diabetic patients. We aimed to study if EMPA could have cardioprotective and anti-inflammatory effects in Doxorubicin (DOXO) - Induced cardiotoxicity. Methods: we tested the effects of EMPA alone or in combination with DOXO in HL-1 adult cardiomyocytes evaluating: mitochondrial viability, lipid peroxidation, Leukotriene-B4 expression, p65-NF-κB activation and Interleukin 1β, 8 and 6 secretion. To evaluate cardiac function, Global Longitudinal Strain (GLS) were measured using 2D speckle tracking echocardiography in C57BL6 mice pretreated with EMPA (10 mg/kg/day) per os for 3 days. EMPA was then administered for additional 7 days, alone and in combination with DOXO (2.25 mg/kg/day ip). Cardiac lysates were processed for analysis of pro-inflammatory Interleukins. Results: EMPA, co-incubated with DOXO, is able to increase the cardiomyocyte viability of 33,6 and 82,3 % at 100 and 500 nM, respectively (compared to only DOXO treated cells). EMPA inhibits the lipid peroxidation by decreasing MDA and 4-HNA production of around 23,6 and 28,7 %, at 100 nM and of 47,8 and 52,1 % at 500 nM, respectively, compared to untreated cells. Moreover, EMPA has anti-inflammatory activity with a reduction of Leukotriene B4 expression and p65-NFkb activation of 58,4 and 64,3 % at 500 nM, respectively (compared to only DOXO treated cells). EMPA also decreased the expression of Interleukin 1β (of 28,5 and 68,8 %), Interleukin-8 (of 21,2 and 57,3 % ) and Interleukin-6 (of 28,1 and 49,8 %) at 100 and 500 nM, respectively, compared to only DOXO exposed cells. Preclinically, after 7 days with DOXO, GLS decreased. Interestingly, in mice treated with EMPA+DOXO, EMPA prevents the GLS’s reduction : GLS was 19.24 ± 1.5 (p < 0,01) vs DOXO alone. In DOXO-EMPA groups, the heart IL-1β, IL-6 and IL-8 tissue extract were reduced of 48, 54,4 and 58,2 % compared to only DOXO groups. Conclusions: EMPA has strong anti-inflammatory and cardioprotective effects in DOXO-Induced cardiotoxicity and these effects are mainly mediated by a reduction of the lipid peroxidation, Leukotriene-B4 and NF-κB activation.