ISSN 2996-8215
International Journal of Cardiology | Vol. 10, No. 5, May 2019 | pp. 33–40
DOI: 10.46882/2019/IJC/000122
Original Research Article
SGLT2 Inhibition with Dapagliflozin Mitigates Myocardial Infarct Size and Attenuates Adverse Left Ventricular Remodeling in a Rat Model of Ischemia-Reperfusion Injury
Heinrich Scholz¹, Klaus Richter¹, Manfred Ziegler²
¹Department of Cardiovascular Pharmacology, University Heart Center Freiburg, Freiburg, Germany
²Division of Experimental Cardiology, Max Delbrück Center for Molecular Medicine, Berlin, Germany
Abstract:
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular death and heart failure hospitalization in clinical trials, yet the localized cellular pathways driving these benefits immediately after ischemic insults remain unresolved. This study investigated the acute cardioprotective effects of dapagliflozin on myocardial infarct size and structural remodeling in a non-diabetic rat model of ischemia-reperfusion (I/R) injury. Male Sprague-Dawley rats were randomized to receive either dapagliflozin (1.5 mg/kg/day, n = 15) or vehicle control (n = 15) via oral gavage for 14 days before undergoing 30 minutes of left anterior descending coronary artery occlusion followed by 24 hours of reperfusion. Infarct size was determined using triphenyltetrazolium chloride staining, and localized inflammation was evaluated via immunohistochemistry. Pretreatment with dapagliflozin significantly limited myocardial infarct size relative to the vehicle control group (28.4% ± 3.2% vs. 44.2% ± 4.1% of the risk area, p < 0.01). Echocardiography at 24 hours revealed a preservation of left ventricular fractional shortening in the dapagliflozin cohort (28.5% ± 2.4% vs. 21.2% ± 1.9%, p < 0.05). Mechanistically, dapagliflozin-treated rats demonstrated a marked reduction in myocardial tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 expression within the border zone. Western blot analysis confirmed a significant down-regulation of cleaved caspase-3 activation alongside up-regulated AMP-activated protein kinase (AMPK) phosphorylation. Dapagliflozin exerts direct, potent cardioprotective actions against acute ischemia-reperfusion injury in non-diabetic rats by mitigating localized inflammatory cell infiltration and suppressing cardiomyocyte apoptotic cascades through active AMPK pathway modulation.
Keywords: Ischemia-reperfusion injury, Dapagliflozin, SGLT2 inhibitors, Infarct size, Apoptosis, Inflammation
Received: February 14, 2019; Revised: March 28, 2019; Accepted: April 12, 2019; Published: May 22, 2019