Elsevier

Toxicology Letters

Volume 182, Issues 1–3, 10 November 2008, Pages 29-35
Toxicology Letters

Chinese medicinal herb Radix Astragali suppresses cardiac contractile dysfunction and inflammation in a rat model of autoimmune myocarditis

https://doi.org/10.1016/j.toxlet.2008.08.002Get rights and content

Abstract

Radix Astragali, a Chinese medicinal herb, consists of polysaccharides and flavonoids as its main active ingredients. It has been widely used for treatment of cardiovascular diseases such as heart failure, angina pectoris, myocardial infarction and stroke in Asian countries. This study was designed to evaluate the effect of Radix Astragali on myocardial dysfunction, cardiac remodeling and morphological alteration in an experimental model of autoimmune myocarditis, a clinical condition often resulting in dilated cardiomyopathy. Experimental autoimmune myocarditis was established with a subcutaneous injection of porcine cardiac myosin into rear footpad in Lewis rats. Radix Astragali treatment was delivered via an intravenous injection (0.2 ml/100 g body weight, daily) for 3 weeks. Results from transthoracic echocardiography indicated that experimental autoimmune myocarditis led to impaired myocardial contractile function which was reconciled by Radix Astragali. The experimental autoimmune myocarditis triggered profound inflammation and fibrosis in myocardium as assessed by hematoxylin and eosin (H and E) and Masson’s trichrome staining. Interestingly, Radix Astragali significantly attenuated autoimmune myocarditis-induced myocardial inflammation and fibrosis. Similarly, Radix Astragali treatment alleviated autoimmune myocarditis-triggered overt lymphocyte proliferation. Furthermore, Radix Astragali significantly attenuated elevated levels of the Th1 cytokines (IFN-γ and IL-2), and increased the Th2 cytokines (IL-4 and IL-10) in autoimmune myocarditis. Collectively, our data revealed that Radix Astragali effectively protected against cardiac functional and morphological aberrations in experimental autoimmune myocarditis.

Introduction

Myocarditis, a heterogeneous myocardial inflammatory disease, leads to both acute and chronic heart failure manifested by dilated cardiomyopathy. The etiology of myocarditis appears to be rather complicated involving idiopathic, infectious or autoimmune factors (Caforio and Iliceto, 2008). Autoimmunity and immune mediators are known to play a critical role in the pathogenesis of an array of cardiovascular diseases leading to compromised ventricular function (Afanasyeva et al., 2004, Maisch et al., 2005). A wide variety of immune cells including CD4 + T cell, CD8 + T cells, granulocytes and mast cells may result in focal myocardial damage en route to cardiomyocyte death, replacement fibrosis and ultimately cardiac contractile dysfunction (Afanasyeva et al., 2004). In addition to apoptosis and fibrosis, other factors such as humoral, cellular immune dysregulation, environmental factors and genetic predisposition have also been consolidated to play a role in the autoimmunity-induced myocardial dysfunction (Maisch et al., 2005). Nonetheless, it is still unclear as to what extent these factors contribute to the immunologically-mediated myocardial damage. Given the poorly defined etiology of autoimmune myocarditis, the current clinical management against this devastating myocardial problem is somewhat dismay with symptom management being the main focus.

Radix Astragali is a traditional Chinese medicinal herb derived from the root of Astragalus membranaceus with polysaccharides and flavonoids being the active constituents (Qi, 1987, Li, 2000). The polysaccharides of Radix Astragali include two glucans, AG-1 (astragalus glucan-1) and AG-2 (astragalus glucan-2), as well as two heteroglycans, AH-1 (astragalus heteroglycan-1 and AH-2 (astragalus heteroglycan-2). The flavonoids comprise predominantly 7,3-dimercapto-4,1-methoxyisoflavone, 3-dimercapto-7,4,1-methoxyisoflavone, catycosin, kumatakenin and fomononetin. Certain amino acids (e.g., folic acid, nicotinamide, and linoleic acid), β-sterol, lupeol, hexanol, palmitic acid, 6-o-β-d-pyranoglucose, 3-o-β-d-xylopyranose and carotenol can also be extracted from A. membranaceus (Qi, 1987, Li, 2000). It has been used clinically for several thousands of years in China and other southeast Asian countries for the treatment of heart, liver and kidney diseases, as well as diabetes mellitus, viral infection and immune disorders (Gui et al., 2006, Chan et al., 2007, Chan et al., 2008, Ai et al., 2008, Ryu et al., 2008, Xu et al., 2008). Pharmacological studies have demonstrated cardiovascular benefit of this product including its cardioprotective effect against heart failure, angina pectoris and myocardial infarction (Chan et al., 2007, Chan et al., 2008, Ryu et al., 2008, Xu et al., 2008). Up-to-date, a number of mechanisms have been speculated for the cardioprotective role of Radix Astragali including improved energy metabolism and antioxidant capacity (Xuejiang et al., 2001). Nonetheless, the precise mechanism(s) of action behind the beneficial effects of Radix Astragali on myocardial injury especially under the condition of autoimmune myocarditis remains elusive.

In the present study, we took advantage of an established experimental model of autoimmune myocarditis model induced by cardiac myosin reminiscent of human myocarditis (Pummerer et al., 1996, Li et al., 2004). Autoimmune myocarditis often develops following acute viral myocarditis in both humans and rodents (Afanasyeva et al., 2004). Experimental autoimmune myocarditis (EAM) induced by cardiac myosin offers a virus-free model to examine the immunopathogenic mechanisms of autoimmune myocarditis with severity peaking around 21 days after immunization (Pummerer et al., 1996, Matsui et al., 2004, Li et al., 2008). The therapeutic potential of Radix Astragali on cardiac myosin-induced experimental autoimmune myocarditis was examined both functionally and morphologically. Considering the close association between proinflammatory cytokines and prevalence of myocardial dysfunction especially in autoimmunity, release of proinflammatory cytokines was monitored in serum from Lewis rats with experimental autoimmune myocarditis in the presence or absence of Radix Astragali treatment.

Section snippets

Experimental animals and research reagents

Twenty-four adult male Lewis rats (6-week-old) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China) and were maintained in the animal facility of the Shandong University School of Medicine. All animals were housed with controlled temperature (22–26 °C), humidity (50–60%) and lighting (with a 12/12 circadian cycle) with free access to standard rat chow and sterile water throughout the duration of our study. All animal experimental procedures were

General features of experimental animals

Body weights were matched for all groups of rats at the time of immunization. Following 3 weeks of autoimmune disease, body weights were significantly lower in the myocarditis group compared with the group, the effect of which was ablated by Radix Astragali treatment. Hearts were significantly enlarged shown in both absolute weight and cardiac size (normalized to body weight) in rats from myocarditis group compared with the control or Radix Astragali-treated myocarditis group. Heart rate was

Discussion

Our current study demonstrated, for the first time, the beneficial effect of Radix Astragali on cardiac dysfunction, morphological changes and cardiac remodeling elicited by an experimental model of autoimmune myocarditis. Radix Astragali treatment abrogated autoimmunity-induced body weight loss and cardiac hypertrophy (both absolute weight and cardiac size) induced by autoimmunity. Transthoracic echocardiography revealed that Radix Astragali abrogated autoimmunity-induced increase of LVDs,

Conflict of interest

None.

Acknowledgments

The authors greatly appreciate Dr. Haitao Yuan for advice and helpful discussion and Xuefei Liu for technical assistance. This work was supported in part by grants from the Natural Science Foundation of Shandong Province (#Y2002C47), Jinan Rising-Star Program (#07112) and Key Technologies R and D Program of Jinan, Shandong Province, China (#200705089-4).

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