Influence of empaglifozin on the heart of rats with myocardial infarction-induced cardiac remodeling

• Grant number: 18/00567-4
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2018
• End date: October 31, 2020
• 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

Despite advance on cardiac remodeling prevention and treatment, mortality after myocardial infarction (MI) is still elevated. The sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce renal glucose reabsorption improving diabetes control. In the EMPA-REG OUTCOME Study, empaglifozin addition to the standard therapy of patients with type 2 diabetes and high risk for cardiovascular disease reduced mortality and the risk for heart failure (HF) hospitalization. Beneficial effects were observed in both HF and non-HF patients, started three months after initiating treatment, and lasted longer than three years. Several effects of SGLT2 inhibitors were described, such as reduction in hyperglycemia, visceral adiposity, serum concentration of insulin, blood pressure, albuminuria, and oxidative stress; attenuation of endothelial dysfunction, and decrease in progression rate of renal disease. However, it seemed unlikely that a slight improvement in glycemia, lipids levels, and blood pressure was responsible for the better outcomes. Therefore, it was suggested that empaglifozin may have direct influence on the cardiovascular system and three hypotheses have been launched to explain the results: 1) a diuretic effect associated with the SGLT2 inhibition and a subsequent reduction in left ventricular (LV) hemodynamic load; 2) changes in cardiac metabolism; and 3) restoration of myocyte sodium and calcium homeostasis. Great interest has emerged on the role of empaglifozin on cardiac metabolism. Furthermore, the results of studies using SGLT2 inhibitors in diabetic patients allowed to raise the hypothesis that this drug class and, particularly, empaglifozin, have protective effects on the cardiovascular system in patients without diabetes. Currently, there are no published studies on renal or cardiovascular effects in non-diabetes patients. Only a few investigators evaluated the effects of SGLT2 inhibitors in experimental cardiac remodeling. We have not found research on the effects of SGLT2 inhibitors on ventricular function after a chronic process of cardiac remodeling. Therefore, to better interpreting clinical trials, it is necessary to evaluate mechanisms involved on SGLT2-induced changes in chronic cardiac remodeling. The purpose of this study is to evaluate the effects of empaglifozin on the heart of normal rats and rats with MI-induced cardiac remodeling. Specifically, we will analyze cardiac structure and function, myocardial metabolism, oxidative stress, and expression of proteins involved in intracellular calcium and sodium transient and in myocyte hypertrophy signaling. MI will be induced by anterior descending coronary artery ligation. Ten days after surgery, transthoracic echocardiogram will be performed to evaluate MI size. Rats with MI lower than 30% of LV size will be excluded. Rats will then be assigned to four groups: Sham (n=15), Sham + empagliflozin (n=15), MI (n=25), and MI + empagliflozin (n=25). Empaglifozin will be added to rat chow (5 mg/kg/day) for 12 weeks. Echocardiogram will be repeated at the final of the experimental period. Myocyte diameters and collagen interstitial fraction will be assessed in LV. Expression of proteins involved in intracellular calcium transient (phospholamban and SERCA2a) and in myocyte hypertrophy (MAPK) will be assessed by Western blot. Oxidative stress and metabolism will be analyzed in LV myocardium. Statistical analyzes will be performed using ANOVA. Comparison between MI size will be evaluated by the Student's t test. Association between variables will be assessed by Pearson or Spearman's correlation. (AU)

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

TARDELLI, LIDIELI P.; DUCHATSCH, FRANCINE; HERRERA, NAIARA A.; VICENTINI, CARLOS ALBERTO; OKOSHI, KATASHI; AMARAL, SANDRA L.. Differential effects of dexamethasone on arterial stiffness, myocardial remodeling and blood pressure between normotensive and spontaneously hypertensive rats. JOURNAL OF APPLIED TOXICOLOGY, FEB 2021. (18/00567-4, 16/12532-5, 17/14405-3, 17/00509-1)

TARDELLI, LIDIELI P. P.; DUCHATSCH, FRANCINE; HERRERA, NAIARA A. A.; RUIZ, THALLES FERNANDO R.; PAGAN, LUANA U. U.; VICENTINI, CARLOS A. A.; OKOSHI, KATASHI; AMARAL, SANDRA L. L.. Benefits of combined exercise training on arterial stiffness and blood pressure in spontaneously hypertensive rats treated or not with dexamethasone. FRONTIERS IN PHYSIOLOGY, v. 13, p. 15-pg., 2022-08-15. (17/14405-3, 17/00509-1, 16/12532-5, 18/00567-4)

TARDELLI, LIDIELI P.; DUCHATSCH, FRANCINE; HERRERA, NAIARA A.; VICENTINI, CARLOS ALBERTO; OKOSHI, KATASHI; AMARAL, SANDRA L.. Differential effects of dexamethasone on arterial stiffness, myocardial remodeling and blood pressure between normotensive and spontaneously hypertensive rats. JOURNAL OF APPLIED TOXICOLOGY, v. 41, n. 10, p. 1673-1686, OCT 2021. (18/00567-4, 16/12532-5, 17/00509-1, 17/14405-3)

DUCHATSCH, FRANCINE; TARDELLI, LIDIELI P.; HERRERA, NAIARA A.; RUIZ, THALLES F. R.; VICENTINI, CARLOS A.; OKOSHI, KATASHI; SANTOS, CARLOS F.; AMARAL, SANDRA L.. Dexamethasone and Training-Induced Cardiac Remodeling Improve Cardiac Function and Arterial Pressure in Spontaneously Hypertensive Rats. JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS, v. 26, n. 2, AUG 2020. (18/00567-4, 15/03965-2, 17/14405-3, 17/00509-1)

ROSA, CAMILA MORENO; SALOME CAMPOS, DIJON HENRIQUE; ABREU REYES, DAVID RAFAEL; DAMATTO, FELIPE CESAR; KUROSAKI, LUCAS YAMADA; PAGAN, LUANA URBANO; GOMES, MARIANA JANINI; CORREA, CAMILA RENATA; HENRIQUE FERNANDES, ANA ANGELICA; OKOSHI, MARINA POLITI; et al. Effects of the SGLT2 Inhibition on Cardiac Remodeling in Streptozotocin-Induced Diabetic Rats, a Model of Type 1 Diabetes Mellitus. ANTIOXIDANTS, v. 11, n. 5, p. 14-pg., 2022-05-01. (18/00567-4, 15/02324-3)