Elsevier

Phytomedicine

Volume 17, Issues 3–4, March 2010, Pages 212-218
Phytomedicine

Tanshinone II A attenuates inflammatory responses of rats with myocardial infarction by reducing MCP-1 expression

https://doi.org/10.1016/j.phymed.2009.08.010Get rights and content

Abstract

The root of Salvia miltiorrhiza Bunge, a well-known traditional Chinese medicine, has been used effectively for the treatment of cardiovascular diseases for a long time. The mechanisms underlying this therapeutic effect are not, however, fully understood. Tanshinone IIA (Tan IIA) is one of the major active components of this Chinese medicine. Therefore, the present study was performed to investigate whether Tan IIA, which has shown a cardio-protective capacity in myocardial ischemia, has an inhibitory effect on the inflammatory responses following myocardial infarction (MI) and its potential mechanisms. In an in vivo study, rat MI model was induced by permanent left anterior descending coronary artery (LAD) ligation. After the operation rats were divided into three groups (sham, MI and Tan IIA). Tan IIA was administered intragastrically at a dose of 60 mg/kg body wt./day. One week later, rats were sacrificed and the hemodynamic, pathological and molecular biological indices were examined. In an in vitro study, the inflammatory model was established by TNF-α stimuli on cardiacmyocyte and cardiac fibroblasts. Tan IIA attenuates the MI pathological changes and improves heart function, and reduces expression of MCP-1, TGF-β1 and macrophage infiltration. Furthermore, Tan IIA could also decrease the expression of TNF-α and activation of nuclear transcription factor-kappa B (NF-κB). In vitro, Tan IIA could reduce MCP-1 and TGF-β1secretion of cardiac fibroblasts. The present study demonstrated that the cardioprotective effects of Tan IIA might be attributed to its capacity for inhibiting inflammatory responses.

Introduction

Myocardial infarction (MI) healing, initiated by acute inflammation, is a critical process for the development of heart pathology. Recent studies have demonstrated that inflammatory responses may cause myocardial damage and fibrosis, leading to progressive impairment of cardiac function post-MI. Particularly, the monocyte chemoattractant protein (MCP)-1, which belongs to the C-C chemokine superfamily, induces the infiltration, activation and cytokine secretion of inflammatory cells. MCP-1 can be induced in numerous cell types, including vascular endothelial cells, smooth muscle cells, monocytes/macrophages and cardiacmyocytes (Xia and Frangogiannis 2007). MCP-1 is markedly upregulated in the infarcted myocardium, both in clinical trials (Kobusiak-Prokopowicz et al. 2007; Arakelyan et al. 2005) and animal models (Dewald et al. 2005; Kohno et al. 2008) of MI. Previous studies found that mice with MCP-1 gene disruption show a greater decrease in macrophage infiltration and the mRNA expression of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β during the healing infarct post-MI than wild-type animals. Consistently, blockade MCP-1 gene attenuated LV cavity dilatation, contractile dysfunction, interstitial fibrosis, recruitment of macrophages and mRNA expression of TNF-α and TGF-β (Hayashidani et al. 2003). Therefore, MCP-1 plays a crucial role in regulation of inflammatory responses and the MI healing process.

The root of Salvia miltiorrhiza Bunge, a well-known traditional Chinese medicine, has been used effectively for the treatment of cardiovascular diseases for a long time. The mechanisms underlying this therapeutic effect are not, however, fully understood. Tanshinone IIA (Tan IIA), as one of the major active components of this Chinese medicine, has been shown to be effective against atherosclerotic calcification (Tang et al. 2007), and apoptosis (Gao et al. 2008) through antioxidative damage (Zhang and Wang 2007; Gao et al. 2008). Tan IIA was also reported to dilate coronary arteries and increase coronary flow by activating potassium channels (Yang et al. 2008; Sun et al. 2008). Additionally, Tan IIA was found to have anti-inflammatory properties (Zhi-yuan et al. 2008). However, whether Tan IIA exerts its cardioprotective action through anti-inflammatory activity is not yet clear. Therefore, the present study determined the effect of Tan IIA on the expression of MCP-1 and TGF-β1 and the inflammatory cytokines, using in vitro and in vivo systems.

Section snippets

Experimental animals and drug

Male Sprague-Dawley rats weighing 200–220 g each were purchased from the Laboratory Animal Institute of Zhejiang Academy of Medical Science, China. Rats were placed in constant conditions at a temperature of 23±3 °C, humidity of 60±5%, under a 12 h light/dark cycle. Rats had free access to a standard diet and drinking water. Tan IIA used in the study was obtained from Laboratory of Plant Resource and Phytochemistry of Zhejiang Univerity, China. The purity of Tan IIA was 98% as determined by high

Effect of Tan IIA on hemodynamic data

Hemodynamic and biochemical data are shown in Table 1. Cardiac systolic and diastolic function were markedly compromised in MI rats (p<0.05). Tan IIA treatment significantly improved systolic and diastolic function, as indicated by reserving LV dp/dtmax and LV dp/dtmin (p <0.01vs MI) and improving LVEDP (p<0.01vs MI ) and LVSP (p <0.01vs MI).

Effect of Tan IIA on infarct size and CVF

Tan IIA treatment significantly decreased infarct size (MI 50.8±4.7%, Tan II A 37.6±10.0%, p <0.05, Figs. 2 A and B). Masson's trichrome staining showed

Discussion

This is the first report providing evidence of Tan IIA anti-inflammatory response following MI. We demonstrated that Tan IIA treatment decreased infarct size markedly, as well as decreasing collagen deposition and improving heart recovery after MI in rats. These effects may be associated with a decrease in the MCP-1and TGF-β1 expression in cardiac fibroblasts as well as macrophage infiltration.

Inhibition of MCP-1 following MI could play an important role in the protective effect of Tan IIA

Acknowledgements

This project was supported by the Natural Science Foundation of Zhejiang Province, China (No: Y207403). We are thankful to Professor Chang-Xin Zhou, Laboratory of Plant Resource and Phytochemistry of Zhejiang Univerity, China, for providing the tanshinone IIA.

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