Abstract
Objective
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.
Methods
A VR model was generated by ligation of coronary artery in rats. Two weeks after surgery, 60 rats 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 rats in each group. Rats 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.
Results
VR rats showed significant dysfunction in hemodynamic indices and cardiac structure and function. Compared with the sham-operation group, myocardial tissue damage, interstitial fibrosis occurred in the model rats, 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 significantly 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).
Conclusion
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.
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Wang L and Huang JL contributed to the conception and design of the study. Xu S and Shi H performed the experiments. Wang L, Shi H, and Liu PP analyzed the data and drafted the paper. All authors read and approved the final version for publication.
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Supported by the National Natural Science Foundation of China (No. 30973707, 81373533, 81202631), the Natural Science Foundation of Anhui Province (No.1508085QH192, 1608085QH222)
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Wang, L., Shi, H., Huang, Jl. et al. Linggui Zhugan Decoction (苓桂术甘汤) Inhibits Ventricular Remodeling after Acute Myocardial Infarction in Rats by Suppressing TGF-β1/Smad Signaling Pathway. Chin. J. Integr. Med. 26, 345–352 (2020). https://doi.org/10.1007/s11655-018-3024-0
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DOI: https://doi.org/10.1007/s11655-018-3024-0