Dapagliflozin Improve Left Ventricular Structure and Function in Mice with Acute Myocardial Infarction
TANG Yi1, ZHU Wenyu1, TAN Siyuan1, ZHANG Min1, XU Xiaoping2, WANG Jiarui3, PENG Jianqiang1
1. Department of Cardiology, Hunan Provincial People's Hospital / The First Affiliated Hospital of Hunan Normal University, Clinical Medicine Research Center of Heart Failure of Hunan Province, Changsha 410005, China; 2. Department of Gastroenterology, Hunan Provincial People's Hospital / The First Affiliated Hospital of Hunan Normal University, Changsha 410005, China; 3. Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
Abstract:ObjectiveTo explore the cardioprotective role of dapagliflozin on acute myocardial infarction mice and its possible mechanism.MethodsEight-week-old male ICR mice were used to construct an acute myocardial infarction model by ligation of the left anterior descending coronary artery and were randomly divided into five groups: (1) Sham group, (2) Model group: acute myocardial infarction group, (3) DAPA group: dapagliflozin treatment group, (4) VAL group: valsartan treatment group; (5) DAPA+VAL group: dapagliflozin combined with valsartan treatment group. After successful modeling, mice were given dapagliflozin valsartan or normal saline by intragastric administration. After 28 days, left ventricular function and structural indexes were measured, myocardial infarct size was measured, myocardial interstitial collagen and collagen volume fraction in infarct area were evaluated, and the expression of nucleotide binding dome-like receptor protein 3(NLRP3) and its related factors were detected.ResultsCompared with the Model group, dapagliflozin and valsartan significantly improved left ventricular structure and function, reduced myocardial infarct area, improved myocardial cell morphology, reduced inflammatory cell infiltration, and inhibited myocardial fibrosis in mice with myocardial infarction. Meanwhile, dapagliflozin and valsartan significantly decreased the expression of NLRP3, interleukin-1β, interleukin-6 in myocardial tissue. However, compared with valsartan alone, dapagliflozin combined with valsartan failed to further improve left ventricular structure and function after acute myocardial infarction as well as the indices mentioned above.ConclusionDapagliflozin can improve left ventricular structure and function. However, the combination of dapagliflozin and valsartan did not further improve left ventricular structure and function compared with valsartan alone.
[1] 中国心血管健康与疾病报告编写组. 中国心血管健康与疾病报告 2020 概要[J]. 中国循环杂志, 2021, 36(06): 521-545. [2] Bahit MC, Kochar A, Granger CB.Post-Myocardial Infarction Heart Failure[J]. JACC Heart Fail, 2018, 6(3): 179-186. [3] Dutka M, Bobiński R, Ulman-Włodarz I, et al.Various aspects of inflammation in heart failure[J]. Heart Fail Rev, 2020, 25(3): 537-548. [4] Ibanez B, James S, Agewall S, et al.2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)[J]. Eur Heart J, 2018, 39(2): 119-177. [5] McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction[J]. N Engl J Med, 2019, 381(21): 1995-2008. [6] Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction[J]. N Engl J Med, 2022, 387(12): 1089-1098. [7] Cunningham JW, Vaduganathan M, Claggett BL, et al.Dapagliflozin in Patients Recently Hospitalized With Heart Failure and Mildly Reduced or Preserved Ejection Fraction[J]. J Am Coll Cardiol, 2022, 80(14): 1302-1310. [8] Liu Y, Wu M, Xu J, et al.Empagliflozin prevents from early cardiac injury post myocardial infarction in non-diabetic mice[J]. Eur J Pharm Sci, 2021, 161: 105788. [9] Wang K, Li Z, Sun Y, et al.Dapagliflozin Improves Cardiac Function, Remodeling, Myocardial Apoptosis, and Inflammatory Cytokines in Mice with Myocardial Infarction[J]. J Cardiovasc Transl Res, 2022, 15(4): 786-796. [10] Toldo S, Marchetti C, Mauro AG, et al.Inhibition of the NLRP3 inflammasome limits the inflammatory injury following myocardial ischemia-reperfusion in the mouse[J]. Int J Cardiol, 2016, 209: 215-220. [11] Byrne N J, Matsumura N, Maayah Z H, et al.Empagliflozin Blunts Worsening Cardiac Dysfunction Associated With Reduced NLRP3(Nucleotide-Binding Domain-Like Receptor Protein 3) Inflammasome Activation in Heart Failure[J]. Circ Heart Fail, 2020, 13(1): e006277. [12] Sutton MG, Sharpe N.Left ventricular remodeling after myocardial infarction: pathophysiology and therapy[J]. Circulation, 2000, 101(25): 2981-2988. [13] Broz P, Dixit VM.Inflammasomes: mechanism of assembly, regulation and signalling[J]. Nat Rev Immunol, 2016, 16(7): 407-420. [14] Toldo S, Mezzaroma E, Muro AG, et al.The inflammasome in myocardial injury and cardiac remodeling[J]. Antioxid Redox Signal, 2015, 22(13): 1146-1161. [15] Kaplanski G.Interleukin-18: Biological properties and role in disease pathogenesis[J]. Immunol Rev, 2018, 281(1): 138-153. [16] Pfeiler S, Winkels H, Kelm M, et al.IL-1 family cytokines in cardiovascular disease[J]. Cytokine, 2019, 122: 154215. [17] Sandanger Ø, Ranheim T, Vinge LE, et al.The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury[J]. Cardiovasc Res, 2013, 99(1): 164-174. [18] Frantz S, Hundertmark MJ, Schulz-Menger J, et al.Left ventricular remodelling post-myocardial infarction: pathophysiology, imaging, and novel therapies[J]. Eur Heart J, 2022; 43(27): 2549-2561. [19] Di Raimondo D, Tuttolomondo A, Buttà C, et al.Effects of ACE-inhibitors and angiotensin receptor blockers on inflammation[J]. Curr Pharm Des, 2012, 18(28): 4385-4413. [20] Dandona P, Dhindsa S, Ghanim H, et al.Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade[J]. J Hum Hypertens, 2007, 21(1): 20-27. [21] J Udell JA, Jones WS, Petrie MC, et al. Sodium Glucose Cotransporter-2 Inhibition for Acute Myocardial Infarction: JACC Review Topic of the Week[J]. J Am Coll Cardiol, 2022, 79(20): 2058-2068.