The Effects of a Meldonium Pre-Treatment on the Sepsis-Induced Rat Heart Injury
2021
Autori:
Lakić, IvaĐurašević, Siniša
Ružičić, Aleksandra
Tosti, Tomislav
Đurović, Saša
Glumac, Sofija
Pavlović, Slađan
Borković Mitić, Slavica
Grigorov, Ilijana
Stanković, Sanja
Jasnić, Nebojša
Todorović, Zoran
Đorđević, Jelena
Tip dokumenta:
Konferencijski prilog (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
Background: Sepsis is a life-threatening condition caused by the dysregulated and overwhelming response to infection, accompanied by exaggerated pro-inflammatory state and lipid metabolism disturbance leading to sequential organ failure.1, 2 Meldonium is an anti-ischemic and anti-inflammatory agent, clinically used to treat myocardial ischemia.3 By shifting energy production from fatty acid oxidation to glycolysis, as an oxygen less consuming pathway, meldonium interferes negatively with lipid metabolism.
Methods: Thus, we investigated the effects of a 4-week meldonium pre-treatment in 300 mg/kg b.m./day dosage on the course of the sepsis induced by a single intraperitoneal injection of faeces (0.5 g faeces/1 mL saline/100 g b.m.)in Sprague-Dawley male rats. The degree of the heart injury was evaluated by measuring tissue pro-apoptotic Bax and anti-apoptotic Bcl-2 ratio, tissue level of the necrotic marker - high mobility group box 1 protein level (HMGB1), together with the heart histology analysis. Sepsis-associated heart inflammation
was assessed by measuring level of an activated form of NF-kB p65 (phospho-NF-κB p65).
Results: In the heart whole homogenates of the septic group of animals (S) HMGB1 level increased 1.7-fold, in comparison to control rats, while meldonium reduced sepsis-induced increase by 18 % (M+S). The underlying mechanism of the proinflammatory action of HMGB1 includes activation of NF-κB signalling
pathways tissue, so the increased HMGB1 level was followed by a 1.4-fold increase of p-NF-κB p65 in the heart of the S group of rats and a 19 % decreased in the heart of M+S group. The apoptotic marker Bax/Bcl-2 ratio changed in the same manner: 1.4-fold increase in the heart of animals from the S group and a 32 % decrease in the heart of the M+S group. On the other hand, heart histology analysis shows that meldonium worsened the heart histological score, causing the severe and diffuse interstitial mononuclear infiltration along with a greater loss of myocytes and myofibrillar contraction band necrosis. The heart lipidomic analysis suggests that meldonium exhibits potentially harmful effects under septic condition due to the lipid-mobilization impairment.
Conclusion: Meldonium exerted anti-inflammatory, anti-apoptotic, and anti- necrotic effects, while it worsened the septic rat heart histology.
Ključne reči:
Sepsis; Heart; Inflammation; Lipidomics; RatFinansiranje / projekti:
- Signalni molekuli u dijabetesu: identifikacija potencijalnih bioloških markera uključenih u modifikaciju i integraciju signalnih puteva u cilju predikcije i intervencije u dijabetesu (RS-MESTD-Basic Research (BR or ON)-173020)
U:
- Abstracts of the 7th Meeting of the European section and 8th Meeting of the North American section of the International academy of cardiovascular sciences (IACS); 2021 Sep 20-23; Banja Luka, Bosnia and Herzegovina. Banja Luka: Association of Medical Doctors; 2021. p. 57. (Scripta Medica; Vol. 52; Suppl. 1).