Journal of Shandong University (Health Sciences) ›› 2022, Vol. 60 ›› Issue (12): 13-18.doi: 10.6040/j.issn.1671-7554.0.2022.0564

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Effects of tolvaptan combined with dapagliflozin on myocardial fibrosis in rats with heart failure

GAO Yan1, ZHU Qingying2, LUAN Mingya1, LIU Kewei1   

  1. 1. Department of General Practice, The 960th Hospital of PLA, Jinan 250031, Shandong, China;
    2. School of Clinical Medicine, Weifang Medical University, Weifang 261053, Shandong, China
  • Published:2022-12-01

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Abstract: Objective To assess the effects of tolvaptan(TLV)and dapagliflozin(DAPA)alone and in combination on the myocardial fibrosis and transforming growth factor-β1(TGF-β1)expression in rats with chronic heart failure. Methods Male Wistar rats were randomly divided into control group, model group, TLV-L group, TLV-H group, DAPA group and TLV-H+DAPA group. Except for the control group, rats in the other groups were given intraperitoneal injection of adriamycin 3 mg/kg once a week for 6 weeks for modeling. After cardiac ultrasound examination of EF<60% indicated successful modeling of heart failure, the rats were randomized into groups and received pharmacological intervention for 30 days. The morphological changes of heart tissue were observed with hematoxylin-eosin(HE)staining; the degree of myocardial fibrosis was detected with Masson staining; the collagen volume fraction(CVF)was calculated; the apoptotic index of myocardial cells was detected with TUNEL staining; the protein expressions of TGF-β1, p-Smad2 and p-Smad3 in the left ventricular myocardial tissue were detected with Western blotting. Results Compared with the control group, the model group showed disordered arrangement of myocardial fibers, more infiltrated inflammatory cells, significant myocardial fibrosis, increased apoptosis, significantly higher protein expression of TGF-β1, and decreased protein expressions of p-Smad2 and p-Smad3(P<0.05). Compared with the model group, the TLV group, DAPA group and TLV-H+DAPA group had significantly reduced myocardial fibrosis and myocardial apoptosis index(P<0.05), significantly reduced protein expression of TGF-β1, and significantly increased protein expressions of p-Smad2 and p-Smad3(P<0.05). Conclusion TLV and DAPA alone and in combination can inhibit myocardial fibrosis by inhibiting the TGF-β1/Smad2/3 signaling pathway, and the effect of combined use is better than that of single drug.

Key words: Tolvaptan, Dapagliflozin, Chronic heart failure, Myocardial fibrosis, Transforming growth factor-β1

CLC Number: 

  • R542.2
[1] Braunwald E. The war against heart failure: the Lancet lecture [J]. Lancet, 2015, 385(9970): 812-824.
[2] Roubille F, Busseuil D, Merlet N, et al. Investigational drugs targeting cardiac fibrosis [J]. Expert Rev Cardiovasc Ther, 2014, 12(1): 111-125.
[3] Matsuzaki M, Hori M, Izumi T, et al. Tolvaptan Investigators. Efficacy and safety of tolvaptan in heart failure patients with volume overload despite the standard treatment with conventional diuretics: a phase III, randomized, double-blind, placebo-controlled study(QUEST study)[J]. Cardiovasc Drugs Ther, 2011, 25(Suppl 1): S33-S45. doi: 10.1007/s10557-011-6304-x.
[4] Hori M. Tolvaptan for the treatment of hyponatremia and hypervolemia in patients with congestive heart failure [J]. Future Cardiol, 2013, 9(2): 163-176.
[5] Packer M. Lessons learned from the DAPA-HF trial concerning the mechanisms of benefit of SGLT2 inhibitors on heart failure events in the context of other large-scale trials nearing completion [J]. Cardiovasc Diabetol, 2019, 18(1): 129.
[6] Joshi SS, Singh T, Newby DE, et al. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure [J]. Heart, 2021, 107(13): 1032-1038.
[7] Schmidt SAJ, Lo S, Hollestein LM. Research techniques made simple: sample size estimation and power calculation [J]. J Invest Dermatol, 2018, 138(8): 1678-1682.
[8] Yamazaki T, Izumi Y, Nakamura Y, et al. Tolvaptan improves left ventricular dysfunction after myocardial infarction in rats [J]. Circ Heart Fail, 2012, 5(6): 794-802.
[9] 徐先静, 黄改荣, 段明勤, 等.托伐普坦对老年慢性心力衰竭合并轻中度肾功能不全伴低钠血症患者的疗效及安全性[J]. 中华老年医学杂志, 2021, 40(3): 292-296. XU Xianjing, HUANG Gairong, DUAN Mingqin, et al. Efficacy of Tolvaptan in elderly chronic heart failure patients combined with mild to moderate renal insufficiency with hyponatremia [J]. Chinese Journal of Geriatrics, 2021, 40(3): 292-296.
[10] Tamaki S, Yamada T, Morita T, et al. Impact of adjunctive tolvaptan on sympathetic activity in acute heart failure with preserved ejection fraction [J]. ESC Heart Fail, 2020, 7(3): 933-937.
[11] Seki T, Kubota Y, Matsuda J, et al. Clinical features and long-term prognosis of patients with congestive heart failure taking tolvaptan: a comparison of patients with preserved and reduced left ventricular ejection fraction [J]. Heart Vessels, 2022, 37(4): 574-582.
[12] Yamazaki T, Nakamura Y, Shiota M, et al. Tolvaptan attenuates left ventricular fibrosis after acute myocardial infarction in rats [J]. J Pharmacol Sci, 2013, 123(1): 58-66.
[13] Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials [J]. Lancet, 2020, 396(10254): 819-829.
[14] Docherty KF, Jhund PS, Claggett B, et al. Extrapolating long-term event-free and overall survival with dapagliflozin in patients with heart failure and reduced ejection fraction: an exploratory analysis of a phase 3 randomized clinical trial [J]. JAMA Cardiol, 2021, 6(11): 1298-1305.
[15] Shi L, Zhu D, Wang S, et al. Dapagliflozin attenuates cardiac remodeling in mice model of cardiac pressure overload [J]. Am J Hypertens, 2019, 32(5): 452-459.
[16] Biernacka A, Dobaczewski M, Frangogiannis NG. TGF-β signaling in fibrosis [J]. Growth Factors, 2011, 29(5):196-202.
[17] Turner NA, Porter KE. Function and fate of myofibroblasts after myocardial infarction [J]. Fibrogenesis Tissue Repair, 2013, 6(1): 5.
[18] 马作旺, 张凯, 王卫定, 等. 托伐普坦通过调控微小RNA-21改善大鼠心房重构[J]. 中华心血管病杂志, 2019, 47(8): 614-621. MA Zuowang, ZHANG Kai, WANG Weiding, et al. Tolvaptan attenuates atrial remodeling in rats undergoing chronic intermittent hypoxia via miRNA-21 [J]. Chinese Journal of Cardiology, 2019, 47(8): 614-621.
[19] Ishikawa M, Kobayashi N, Sugiyama F, et al. Renoprotective effect of vasopressin v2 receptor antagonist tolvaptan in Dahl rats with end-stage heart failure [J]. Int Heart J, 2013, 54(2): 98-106.
[20] Zhang Y, Lin X, Chu Y, et al. Dapagliflozin: a sodium-glucose cotransporter 2 inhibitor, attenuates angiotensin II-induced cardiac fibrotic remodeling by regulating TGFβ1/Smad signaling [J]. Cardiovasc Diabetol, 2021, 20(1): 121.
[21] Tingting H, Guangzhong L, Yanxiang Z, et al. Qiliqiangxin attenuates atrial structural remodeling in prolonged pacing-induced atrial fibrillation in rabbits [J]. Naunyn Schmiedebergs Arch Pharmacol, 2019, 392(5): 585-592.
[22] Cui L, Wang Y, Yu R, et al. Jia-Shen decoction-medicated serum inhibits angiotensin-II induced cardiac fibroblast proliferation via the TGF-β1/Smad signaling pathway [J]. Mol Med Rep, 2016, 14(2): 1610-1616.
[23] Su HH, Liao JM, Wang YH, et al. Exogenous GDF11 attenuates non-canonical TGF-β signaling to protect the heart from acute myocardial ischemia-reperfusion injury [J]. Basic Res Cardiol, 2019, 114(3): 20.
[24] Subrahmanian S, Varshney R, Subramani K, et al. N-Acetylcysteine inhibits aortic stenosis progression in a murine model by blocking shear-induced activation of platelet latent transforming growth factor Beta 1 [J]. Antioxid Redox Signal, 2021, 7. doi: 10.1089/ars.2021.0037.
[25] Peng MZ, Yang ML, Shen AL, et al. Huoxin pill attenuates cardiac fibrosis by suppressing TGF-β1/Smad2/3 pathway in isoproterenol-induced heart failure rats [J]. Chin J Integr Med, 2021, 27(6): 424-431.
[26] García R, Nistal JF, Merino D, et al. p-SMAD2/3 and DICER promote pre-miR-21 processing during pressure overload-associated myocardial remodeling [J]. Biochim Biophys Acta, 2015, 1852(7): 1520-1530.
[27] Chen W, He S, Xiang D. Hypoxia-induced retinal pigment epithelium cell-derived bFGF promotes the migration and angiogenesis of HUVECs through regulating TGF-β1/smad2/3 pathway [J]. Gene, 2021,790: 145695. doi: 10.1016/j.gene.2021.145695.
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