Journal Article Ahead of print
PubMed: 41995817 DOI: 10.1007/s00395-026-01177-6
Empagliflozin improves metabolism and prevents myocardial and coronary dysfunction in streptozotocin-diabetic and non-diabetic rats subjected to ischemia/reperfusion.
Basic Res Cardiol
Authors: Carmine Rocca, Anna De Bartolo, Maria Concetta Granieri, Vittoria Rago, Francesco Conforti, Lidia Urlandini, Naomi Romeo, Letizia Mattii, Raffaele De Caterina, Pasquale Pagliaro, Tommaso Angelone, Claudia Penna, Rosalinda Madonna
Affiliations
- Cellular and Molecular Cardiovascular Physiology and Pathophysiology Laboratory, Department of Biology, E. and E. S. (DiBEST), University of Calabria, Rende, Cosenza, Italy.
- National Institute of Cardiovascular Research (INRC), Bologna, Italy.
- Human Anatomy Laboratory, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
- Pathology Unit, Annunziata Hospital, Cosenza, Italy.
- Department of Clinical and Experimental Medicine, University of Pisa, 56124, Pisa, Italy.
- Department of Surgical, Medical and Molecular Pathology and Critical Area, Cardiology Division, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy.
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy.
- National Institute of Cardiovascular Research (INRC), Bologna, Italy.
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy.
- Department of Surgical, Medical and Molecular Pathology and Critical Area, Cardiology Division, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy.
Abstract
Diabetes heightens cardiovascular risk. The selective sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) shows cardiovascular benefits in heart failure, type 2 diabetes and chronic kidney disease. While EMPA protects against myocardial ischemia/reperfusion injury (MIRI) in diabetic and non-diabetic hearts, its mechanisms and impact on specific endpoints, including autophagy, angiocrine signaling, and metabolic flexibility, remain incompletely defined. We explored the systemic and myocardial effects of chronic EMPA pretreatment on these endpoints in diabetic and non-diabetic animals subjected to MIRI. In streptozotocin (STZ, 65 mg/kg) diabetic rats, EMPA (15 mg/kg/d, 4 weeks) reduced water intake without affecting hyperphagia or weight loss. EMPA ameliorated glucose and lipid profiles, tended to restore myocardial GLUT4 and counteract alterations in myocardial hydroxymethylglutaryl-CoA synthase (HMGCS2) and 3-oxoacid CoA-transferase 1 (OXCT1) levels. EMPA improved biomarkers of myocardial damage (BNP, NT-proBNP, CK-MB, galectin 3), inflammation (cardiac NLRP3, plasma IL-1β), oxidative stress (plasma SOD and malondialdehyde), angiocrine imbalance (VEGF and apelin), fibrosis, and collagen deposition, while showing a tendency to improve autophagy and apoptosis signaling. Ex vivo, EMPA improved baseline contractility and post-ischemic recovery of left ventricular pressure (dLVP from baseline: ~+4% in STZ+EMPA vs. -25% in STZ; ~+3% in EMPA vs. -28% in MIRI), enhanced coronary flow recovery, and reduced cardiac contracture, infarct size, and coronary LDH leakage in both diabetic and non-diabetic hearts. These effects may be associated with post-ischemic histological improvements, reduced vascular congestion, increased eNOS phosphorylation, activation of cardioprotective pathways, and inhibition of mPTP opening. Consistently, EMPA enhances wound healing and preserves eNOS phosphorylation in high-glucose (HG) human cardiac microvascular endothelial cells. In human cardiomyocytes, EMPA reduced hypoxia/reoxygenation (H/R) cell death, preserved nitrate and nitrite levels-effects abolished in the presence of L-NAME-and improved mitochondrial membrane potential in HG and/or H/R conditions. EMPA improved metabolic health and protected myocardial and coronary function likely via a permissive microvascular and myocardial phenotype that limits reperfusion injury, supporting its use against MIRI in normal and diabetic settings.
MeSH
Cells, Autophagy, Heart, Cardiovascular System, Recycling, Cardiology, Streptozocin, Reperfusion, Reperfusion Injury, Ischemia, Plasma