Sodium-glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy

• Published in: Cardiovascular diabetology 2020-01, Vol.19 (1), p.7-12, Article 7
• Main Authors: Arow, M, Waldman, M, Yadin, D, Nudelman, V, Shainberg, A, Abraham, N G, Freimark, D, Kornowski, R, Aravot, D, Hochhauser, E, Arad, M
• Format: Article
• Language: English
• Subjects: Angiotensin; Angiotensin II; Animals; Antidiabetics; Benzhydryl Compounds - pharmacology; Biomarkers - blood; Blood Glucose - drug effects; Blood Glucose - metabolism; Blood pressure; Calcium; Calcium (intracellular); Calcium channels; Calcium channels (L-type); Calcium channels (voltage-gated); Calcium Channels, L-Type - metabolism; Calcium Signaling - drug effects; Calcium transport; Calcium transport fibrosis; Cardiomyocytes; Cardiomyopathy; Cardiovascular disease; Cardiovascular diseases; Cell culture; Cells, Cultured; Collagen; Congestive heart failure; Coronary artery disease; Dapagliflozin; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus - blood; Diabetes Mellitus - drug therapy; Diabetes mellitus type 2; Diabetic Cardiomyopathies - chemically induced; Diabetic Cardiomyopathies - metabolism; Diabetic Cardiomyopathies - physiopathology; Diabetic Cardiomyopathies - prevention & control; Disease Models, Animal; Drinking water; Drug dosages; Fibrosis; Fluorescent indicators; Glucose; Glucose transporter; Glucosides - pharmacology; Heart failure; Homeostasis; Hypertrophy; Indo-1; Inflammation; Inflammation Mediators - metabolism; Intracellular; Kidneys; Male; Membrane channels; Mice, Inbred C57BL; Mortality; Mutation; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Na+/Ca2+ exchanger; Na+/H+-exchanging ATPase; Original Investigation; Oxidative stress; Rats, Sprague-Dawley; Risk factors; Rodents; Sodium; Sodium-Calcium Exchanger - metabolism; Sodium-glucose cotransporter; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Sodium-Hydrogen Exchanger 1 - metabolism; Ventricle; Ventricular Function, Left - drug effects
• ISSN: 1475-2840; 1475-2840
• DOI: 10.1186/s12933-019-0980-4

Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2 inhibitors (SGLT2I) are recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin-SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2. Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin II (ATII) for 30 days using an osmotic pump. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water. Male homozygous, 12-14 weeks old WT or db/db mice (n = 4-8/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5-33 mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1. Angiotensin II infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNFα, TLR4). Dapagliflozin decreased blood glucose (874 ± 111 to 556 ± 57 mg/dl, p