Influence of empagliflozin on the myocardium of rats with heart failure induced by aortic stenosis

• Grant number: 21/10923-5
• Support Opportunities: Regular Research Grants
• Duration: July 01, 2022 - September 30, 2024
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Katashi Okoshi
• Grantee: Katashi Okoshi
• Host Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Associated researchers: Marina Politi Okoshi

Abstract

Heart failure (HF) is clinically characterized by a reduced capacity for physical exercise and daily activities. HF is caused by diseases such as systemic arterial hypertension, myocardial infarction, valve disease, and cardiomyopathy. Chronic hemodynamic overload produced by these diseases induces genetic, molecular, cellular and interstitial changes that manifest clinically as alterations in the size, shape, and function of the heart, a process known as cardiac remodeling. The hemodynamic overload can lead to changes in the collagen architecture, induce fibrosis, and cause an imbalance between the production of reactive oxygen species (ROS) and the antioxidant capacity. These alterations contribute to the cardiac remodeling process and impair the HF clinical picture. Due to the high morbidity and mortality associated with HF, there is great interest in the development of new drugs to attenuate cardiac remodeling. More recently, it has been observed that sodium-glucose cotransporter-2 (SGLT2) inhibitors, initially prescribed in the treatment of diabetes mellitus, have cardioprotective effects; however, their underlying mechanisms are still unclear. The aim of this study is to evaluate the influence of empagliflozin on functional, structural and molecular changes in the myocardium of rats with heart failure induced by aortic stenosis. Methods: Eighteen weeks after aortic stenosis induction, four experimental groups of male Wistar rats will be assigned: Sham (n=15); sham + empagliflozin (S+EMPA, n=15); aortic stenosis (AE, n=25); aortic stenosis + empagliflozin (AE+EMPA, n=25). The rats of groups S+EMPA and AE+EMPA will receive empagliflozin (10 mg/kg/day) added to their diet, for 8 weeks. In vivo cardiac evaluation will be performed by echocardiography. Left ventricular tissue samples will be obtained for biochemical, histological, and molecular analysis. In vitro, H9C2 cells will be induced by oxidative stress by H2O2 and treated with emplaglifozin. After treatment, they will undergo immunofluorescence (Nfr2) and Western blotting (antioxidant enzymes, MAPKs, NF-kB, TNF-±, IL-6) analyzes. Comparisons between groups will be performed by ANOVA and Bonferroni for normal distribution data, or Kruskal-Wallis and Dunn for non-normal distribution data. Significance level will be set at 5%. (AU)