Natural products with anti-inflammatory and immunomodulatory activities against autoimmune myocarditis

Abstract

Myocarditis is an inflammatory disease of the myocardium associated with immune dysfunction which may frequently lead to the development of dilated cardiomyopathy. Experimental autoimmune myocarditis is an animal model which mimics myocarditis in order to allow assessment of the therapeutic effects of different molecules on this disease. We aimed to review the inflammatory and immunological mechanisms involved in the pathogenesis of the myocarditis and finding natural products and phytochemicals with anti-myocarditis activities based on studies of cardiac myosin-induced experimental autoimmune myocarditis in rodents. A number of natural molecules (e.g. apigenin, berberine and quercetin) along with some plant extracts were found to be effective in alleviating experimental autoimmune myocarditis. Upregulation of Th1-type cytokines and elevation of the Th2-type cytokines (IL-4 and IL-10), mitigation of oxidative stress, modulation of mitogen-activated protein kinase signaling pathways and increasing Sarco-endoplasmic reticulum Ca²⁺-ATPase levels are among the most important anti-myocarditis mechanisms for the retrieved molecules and extracts. Interestingly, there are structural similarities between the anti-EAM compounds, suggesting the presence of similar pharmacophore and enzymatic targets for these molecules. Naturally occurring molecules discussed in the present article are potential anti-myocarditis drugs and future additional animal studies and clinical trials would shed more light on their effectiveness in the treatment of myocarditis and prevention of dilated cardiomyopathy.

Introduction

Myocarditis is an inflammatory disease of the myocardium associated with immune dysfunction which may frequently lead to the development of dilated cardiomyopathy (DCM) [1]. Myocarditis is diagnosed by endomyocardial biopsy using established immunological, histological and immunohistochemical criteria [2]. The incidence of myocarditis has been difficult to determine because clinical presentations of the disease vary widely. However, autopsy reports have revealed varying estimates ranging from 0.12% to 12%, according to the population studied [3]. Approximately 21% of acute myocarditis patients develop DCM [4]. Lymphocytes and mononuclear cells infiltration, enhanced pro-inflammatory chemokines, cytokines and circulating autoantibodies expression are frequently observed in myocarditis and DCM [5]. Some patients with myocarditis develop a fulminant course followed by death from intractable cardiogenic shock. Unfortunately, no effective treatment strategy for myocarditis has still been introduced [6].

Experimental autoimmune myocarditis (EAM) is a CD4⁺ T-cell-mediated disorder involving a Th1/Th2 imbalance. It is an animal model of myocarditis induced by immunizing them with cardiac myosin together with complete Freund’s adjuvant [7], [8]. Cardiac tissue obtained from EAM animals demonstrates enlargement of the heart, dilatation of ventricles, severe myocardial injuries and large areas of myocyte fibrosis similar to those observed in human myocarditis [5], [8], [9]. This model has been largely used to mimic moycaritis in order to investigate the effects of different molecules on this disease. Medicinal plants and natural products have long been used to manage various diseases. Traditional Medical systems such as Persian Medicine, Chinese Traditional Medicine and Ayurvedic Medicine have used plants to alleviate and cure a wide range of cardiovascular problems [10], [11]. Many studies investigated the role of medicinal plants and phytochemicals in alleviating EAM severity. The aim of this article is to review natural products and phytochemicals with antimyocarditis activities based on studies of cardiac myosin (CM)-induced experimental autoimmune myocarditis (EAM) in rodents. The inflammatory and immunological mechanisms involved in the pathogenesis of the myocarditis are also discussed.