Linggui Zhugan Decoction (苓桂术甘汤) Inhibits Ventricular Remodeling after Acute Myocardial Infarction in Rats by Suppressing TGF-β 1/Smad Signaling Pathway

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 m RNA and proteins expression in transforming growth factor-beta 1(TGF-β_1)/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 Power Lab data acquisition and analysis recording instrument. Morphology changes of myocardial tissue were observed by hematoxylin-eosin and Masson staining. The expressions of TGF-β_1, Smad2, Smad3, p-Smad2 and p-Smad3 in myocardial tissue were detected by Western blotting. The m RNA expressions of TGF-β_1, Smad2 and Smad3 were detected by reverse transcription-quantitative polymerase chain reaction(RT-q PCR). 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 shamoperation group, myocardial tissue damage, interstitial fibrosis occurred in the model rats, left ventricular systolic pressure(LVSP), left ventricular pressure maximum contraction rate(+dp/dt_(max)) and left ventricular pressure maximum relaxation rate(-dp/dt_(max)) decreased significantly(all P0.01), while left ventricular end-diastolic pressure(LVEDP), cardiac weight index and left ventricular weight index elevated significantly, meanwhile TGF-β_1, p-Smad2, p-Smad3, Smad2, Smad3, MMP2, MMP9, collagen Ⅰ, collagen Ⅲ protein expressions in myocardial tissue and TGF-β_1, Smad2 and Smad3 m RNA expressions increased significantly(all P0.01). Compared with the model group, LZD could significantly improve the pathological changes of myocardial tissue, increase LVSP, +dp/dt_(max) and-dp/dt_(max), lower LVEDP, reduce the whole heart weight index and left ventricular weight index and inhibit the over-expressions of TGF-β_1, p-Smad2, p-Smad3, Smad2, Smad3, MMP2, MMP9, collagen Ⅰ and collagen Ⅲ proteins in myocardial tissue and m RNA expressions of TGF-β_1, Smad2 and Smad3(P0.05 or P0.01). Conclusion: LZD can significantly suppress VR induced by AMI, and its underlying mechanism may be associated with its inhibitory effect on the TGF-β_1/Smad signaling pathway.