ISSN 2996-8215
International Journal of Cardiology | Vol. 13, No. 1, January 2022 | pp. 1–8
DOI: 10.46882/2022/IJC/000154
Original Research Article
Cardioprotective Action of Ipragliflozin against Myocardial Remodeling via Suppression of Left Ventricular Interstitial Fibrosis
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 improve functional clinical parameters in heart failure cohorts, but the structural tissue modifications driving these benefits require clarification in post-ischemic hearts. This study evaluated the structural and molecular cardioprotective actions of ipragliflozin on chronic ventricular dilation and left ventricular (LV) interstitial fibrosis in a non-diabetic rat model of ischemic heart failure. Myocardial infarction was induced in adult male Wistar rats via permanent ligation of the left anterior descending coronary artery. Four weeks post-ligation, rats showing an echocardiographically verified LVEF less than 40% were randomized 1:1 to receive ipragliflozin (3.0 mg/kg/day, n = 15) or vehicle control (n = 15) via oral gavage for 8 consecutive weeks. Ipragliflozin administration significantly preserved baseline LVEF compared to the vehicle arm (41.4% ± 3.2% vs. 34.6% ± 2.8%, p < 0.05) and limited progressive left ventricular diastolic expansion. Histological quantification via Masson's trichrome staining showed a distinct reduction in the collagen volume fraction within non-infarcted remote myocardial regions (3.6% ± 0.5% vs. 5.4% ± 0.8%, p < 0.01). Western blot assays confirmed that ipragliflozin significantly down-regulated transforming growth factor-beta-1 (TGF-beta-1) expression, suppressing the activation of pro-fibrotic Smad3 signaling pathways in isolated cells. Ipragliflozin exerts direct structural cardioprotective actions against adverse post-ischemic left ventricular remodeling in rats by actively attenuating interstitial collagen deposition through the inhibition of profibrotic TGF-beta-1 pathways.
Keywords: Ischemic heart failure, Ipragliflozin, SGLT2 inhibitors, Interstitial fibrosis, Left ventricular remodeling, Animal model
Received: October 12, 2021; Revised: November 25, 2021; Accepted: December 15, 2021; Published: January 22, 2022