Linggui Zhugan Decoction (苓桂术甘汤) Inhibits Ventricular Remodeling after Acute Myocardial Infarction in Mice by Suppressing TGF-β1/Smad Signaling Pathway
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To investigate the inhibitory effect of Linggui Zhugan Decoction (LZD, 苓桂术甘汤) on the ventricular remodeling (VR) after acute myocardial infarction (AMI) and related mRNA and proteins expression in transforming growth factor-beta 1 (TGF-β1)/Smad signaling pathway, and explain its putative mechanism.
A VR model was generated by ligation of coronary artery in mice. Two weeks after surgery, 60 mice were randomly divided into the model group, the sham-operation group (distilled water), the positive control group (2.4 mg/kg simvastatin), and the low-, medium- and high-dose LZD groups (2.1, 4.2, 8.4 g crude drug/kg, respectively) by a random number table, 10 mice in each group. Mice in each group was treated for 4 weeks. Changes of hemodynamics indices and cardiac weight index were detected by the PowerLab data acquisition and analysis recording instrument. Morphology changes of myocardial tissue were observed by hematoxylin-eosin and Masson staining. The expressions of TGF-β1, Smad2, Smad3, p-Smad2 and p-Smad3 in myocardial tissue were detected by Western blotting. The mRNA expressions of TGF-β1, Smad2 and Smad3 were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expressions of matrix metalloprotein 2 (MMP2), MMP9, collagen I and collagen III were observed by immunohistochemical methods.
VR mice showed significant dysfunction in hemodynamic indices and cardiac structure and function. Compared with the shamoperation group, myocardial tissue damage, interstitial fibrosis occurred in the model mice, left ventricular systolic pressure (LVSP), left ventricular pressure maximum contraction rate (+dp/dtmax) and left ventricular pressure maximum relaxation rate (-dp/dtmax) decreased significantly (all P<0.01), while left ventricular end-diastolic pressure (LVEDP), cardiac weight index and left ventricular weight index elevated significantly, meanwhile TGF-β1, p-Smad2, p-Smad3, Smad2, Smad3, MMP2, MMP9, collagen I, collagen III protein expressions in myocardial tissue and TGF-β1, Smad2 and Smad3 mRNA expressions increased significantly (all P<0.01). Compared with the model group, LZD could signififi cantly improve the pathological changes of myocardial tissue, increase LVSP, +dp/dtmax and -dp/dtmax, lower LVEDP, reduce the whole heart weight index and left ventricular weight index and inhibit the over-expressions of TGF-β1, p-Smad2, p-Smad3, Smad2, Smad3, MMP2, MMP9, collagen I and collagen III proteins in myocardial tissue and mRNA expressions of TGF-β1, Smad2 and Smad3 (P<0.05 or P<0.01).
LZD can significantly suppress VR induced by AMI, and its underlying mechanism may be associated with its inhibitory effect on the TGF-β1/Smad signaling pathway.
KeywordsLinggui Zhugan Decoction acute myocardial infarction ventricular remodeling transforming growth factor-beta 1/Smad signaling pathway Chinese medicine
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- 1.Zhao ZQ, Mao JY. Current situation and prospect of the application of traditional Chinese medicine on treatment of chronic heart failure. Chin J Tradit Chin Med Pharm (Chin) 2012;27:2253–2257.Google Scholar
- 2.Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guideline. Circulation 2013;128:1810–1852.CrossRefGoogle Scholar
- 3.Huang J, Yang FJ, Zhang J. Guidelines for diagnosis and treatment of heart failure in China (2014). Chin J Cardiol (Chin) 2014;42:98–122.Google Scholar
- 4.Rao SV, Zeymer U, Douglas PS, Al–Khalidi H, Liu J, Gibson CM, et al. A randomized, double–blind, placebocontrolled trial to evaluate the safety and effectiveness of intracoronary application of a novel bioabsorbable cardiac matrix for the prevention of ventricular remodeling after large ST–segment elevation myocardial infarction: rationale and design of the PRESERVATION trial. Amer Heart J 2015;170:929–937.CrossRefGoogle Scholar
- 5.Lv QQ, Song JS. Literature study on spectrum of prescriptions for treating arrhythmia in treatise on cold pathogenic and miscellaneous diseases. J Tradit Chin Med (Chin) 2017;58:878–883.Google Scholar
- 6.Huang LF, Chen M. Meta–analysis of randomized clinical trials for Linggui Zhugan Decoction on the treatment of congestive heart failure. J Yunnan Univer Tradit Chin Med (Chin) 2016;39:59–69.Google Scholar
- 7.Yu LT, Xu H, Duan WH, Qu WB, Xia JY, Lin Q. Researching Academician Chen Ke–ji's law associated with the use and combination of Chinese medicine in treatments of chronic heart failure based on the scale–free network. Chin J Integr Trad West Med (Chin) 2018;38:1045–1048.Google Scholar
- 8.Liu YF, Liu Y, Yao HZ, Sun MY, Gao R. Current evidence of Lingguizhugan Decoction as TCM prescription: a bibliometricsbased review. World Chin Med 2017;12:1466–1474.Google Scholar
- 9.Wang L, Hou XY, Huang JL, Bao YL, Shi H, Fang HY, et al. Effects of Ling–gui–zhu–gan Decoction on Ang, Ald and AT1R in rats of ventricular remodeling after acute myocardial infarction. Chin J Basic Med Tradit Chin Med (Chin) 2012;18:624–626.Google Scholar
- 10.Wang L, Hou XY, Bao YL, Huang JL, Fang HY, Shi H, et al. Effects of Ling–gui–zhu–gan Decoction on TNF–α, IL–6 and ET–1 of rats with ventricular remodeling for acute myocardial infarction. J Shanxi Coll Tradit Chin Med (Chin) 2012;13:10–12.Google Scholar
- 12.Wang L, Hou XY, Huang JL, Wang TS, Bao YL, Shi H. Effects of Ling–gui–zhu–gan Decoction on TNF–α in myocardium and NF–κB, IL–1β in serum of model rats with chronic heart failure. Chin Tradit Herb Drugs (Chin) 2013;44:586–589.Google Scholar
- 13.Huang JL, Wang HH, Chen HF, Wu DL, Liu XH, Wang TS, et al. Optimization of extraction technology for Ling–gui–zhugan Decoction by orthogonal test. J Anhui Coll Tradit Chin Med (Chin) 2011;30:65–67.Google Scholar
- 14.Wang Q, Wu DL, Huang JL, Zhang W, Liu XH, Wang TS. Optimization of water extraction process for preparing Linggui Zhugan Granules by multi–index orthogonal test. J Anhui Coll Tradit Chin Med (Chin) 2013;32:87–90.Google Scholar
- 15.Zhang Q, Zhao D, Xie W, Guo M, Wang M, Wang W, et al. Recent trends in hospitalization for acute myocardial infarction in Beijing: increasing overall burden and a transition from ST–segment elevation to non–ST–segment elevation myocardial infarction in a population–based study. Medicine 2016;95:26–31.CrossRefGoogle Scholar
- 18.Yan JT, Liu XQ, Liang YX, Liu M, Li CW, Wang QG. Professor Liu Duzhou's clinical experience on treating gout. Chin Arch Tradit Chin Med (Chin) 2012;30:1066–1068.Google Scholar
- 20.Gu SM, Wu ZG, Wei M, Zhang JJ, Wu YH, Liu MY, et al. Change of cardiac matrix metalloproteinases during the progression of left ventricular remodeling in a rat model of acute myocardial infarction. Shanghai Med J (Chin) 2004;27:670–673.Google Scholar
- 21.Chen YL, Sun CK, Tai TH, Chang LT, Leu S, Zhen YY, et al. Adipose–derived mesenchymal stem cells embedded in plateletrich fibrin scaffolds promote angiogenesis, preserve heart function, and reduce left ventricular remodeling in rat acute myocardial infarction. Amer J Trans Res 2015;7:781–803.Google Scholar