Part 1 Effects And Mechanisms Of Chinese Herbal Medicine in Ameliorating Myocardial Ischemia-Reperfusion Injury

Qing Liu,1,2 Jiqiang Li,2 Jing Wang,2 Jianping Li,1 Joseph S. Janicki,1 and Daping Fan1

1 Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA

2 The Second Clinical School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China

Correspondence should be addressed to Daping Fan; daping.fan@uscmed.sc.edu Received 24 July 2013; Revised 26 August 2013; Accepted 4 September 2013 Academic Editor: John-Rong Sheu

Copyright © 2013 Qing Liu et al. This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Myocardial ischemia-reperfusion (MIR) injury is a major contributor to the morbidity and mortality associated with coronary artery disease, which accounts for approximately 450,000 deaths a year in the United States alone. Chinese herbal medicine, especially combined herbal formulations, has been widely used in traditional Chinese medicine for the treatment of myocardial infarction for hundreds of years. While the efficacy of Chinese herbal medicine is well documented, the underlying molecular mechanisms remain elusive. In this review, we highlight recent studies which are focused on elucidating the cellular and molecular mechanisms using extracted compounds, single herbs, or herbal formulations in experimental settings. These studies represent recent efforts to bridge the gap between the enigma of ancient Chinese herbal medicine and the concepts of modern cell and molecular biology in the treatment of myocardial infarction.

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1. Introduction

Myocardial infarction (MI) and the accompanying acute loss of viable myocardium is the leading cause of death in industrialized countries. Even if the patient survives the acute phase of MI, the subsequent adverse myocardial remodeling and impairment of cardiac function severely impact their quality of life and 5-year survival. Early restoration of blood flow to the ischemic myocardium is a common treatment strategy aimed at limiting myocardial infarct size. However, reperfusion can cause additional cell death and, in many cases, paradoxically increase infarct size, a situation referred to as myocardial ischemia-reperfusion (MIR) injury. MIR is characterized by a rapid increase in cytokines and chemokines and an influx of leukocytes into the vulnerable region bordering the infarcted site. This inflammatory response not only results in cardiomyocyte apoptosis during the acute phase but also results in an adverse myocardial remodeling that further compromises cardiac function. Therefore, limiting ischemia-reperfusion (I/R) induced myocardial inflammation may not only lower the acute death rate but also improve long-term survival and quality of life [1]. Chinese herbal medicine, especially combined herba formulations has been widely used in traditional Chinese medicine for the treatment of MI for hundreds of years. The purpose of this review is to highlight recent studies that experimentally address the mechanistic effects of extracted compounds, single herbs, or herbal formulations on several factors and pathways known to be involved in MIR injury.

2. Myocardial Ischemia-Reperfusion Injury

2.1. Oxidative Stress.

Reactive oxygen species (ROS) have both a physiological and pathological role in cellular and tissue adaptation to environmental factors. Normally, low levels of oxygen radicals and oxidants are present in cells and are important in maintaining cellular homeostasis, mitosis, differentiation, and signaling [2]. However, during MIR, ROS formation is markedly increased and cellular injury occurs (Figure 1). Although mammalian cells express endogenous free radical scavenging enzymes, such as superoxide dis- mutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), these antioxidative defenses are insufficient during MIR [3, 4]. Oxidative stress during MIR injury contributes to a vicious cycle as it promotes mitochondrial dysfunction, excitotoxicity, lipid peroxidation, and inflammation [5–7].

2.2. Sterile Inflammation.

Ischemia and reperfusion cause sterile inflammation. Nevertheless, the consequences of MIR share many phenotypic parallels with activation of a host immune response directed toward invading microorganisms [8]. This sterile inflammation is mainly triggered by the interactions between toll-like receptors (TLRs) and their endogenous ligands generated in ischemic and reperfused myocardium, such as apoptotic cell debris, fibrinogen, high mobility group box (HMGB) 1, and heat shock proteins (HSPs) [9]. The activation of immune cell and cardiomyocyte TLR and other signaling pathways results in a vicious cycle of inflammatory response in the I/R region and causes significant cardiomyocyte apoptosis (Figure 1). Following the acute I/R period, cardiac function is further compromised by adverse myocardial remodeling [10]. The magnitude of the inflammation during the acute phase determines the extent to which cardiac function is compromised during the following myocardial remodeling phase. During the sterile inflammation phase of MIR, TLRs play detrimental roles as demonstrated by extensive experimental evidence [11]. To date, 11 TLRs (TLR1–TLR11) have been identified in mammals. It should be noted that, during MIR, the expression of TLR4 is significantly increased in both the failing myocardium and infiltrated macrophages and thus TLR4 is thought to be a central mediator of inflammation and cardiac injury. TLR4 has been identified as a mediator of inflammation and organ injury in several models of sterile tissue injury including MIR, and a soluble inhibitor of TLR4 was able to prevent contractile dysfunction in wild-type cells [12]. Using a temporary left anterior descending (LAD) artery occlusion model, Oyama et al. first observed myocardial infarct size reductions in 2 distinct strains of mice that lack functional TLR4 signaling, accompanied with reduced neutrophil infiltration in the affected myocardium [13]. TLR2, which is expressed in cardiomyocytes and many other cell types, also contributes to the pathogenesis of cardiac dysfunction during MIR [14, 15]. Activation of TLR2, TLR4, and TLR5 increases the myocardial level of the inflammatory cytokines, chemokines, and cell surface adhesion molecules [16]. Given the known role of TLR4 and TLR2 in MIR, inhibition of TLR4 and TLR2 signaling is a promising approach to reduce morbidity and mortality in MI patients. There are a variety of TLR ligands generated during MIR. For example, heat shock proteins (HSPs) are a class of molecular chaperones that promote intracellular protein folding. They may be released into the extracellular space after cell trauma and interact with adjacent cells or distant cells via bloodstream delivery [17]. Extracellular HSP60 induced apoptosis via the activation of TLRs [18]. Another example is HMGB1 which is a damage-associated molecular pattern (DAMP) protein secreted by injured cells [19]. It plays a major role in early MIR by binding to TLRs and the receptor for advanced glycation end products (RAGE), resulting in the activation of proinflammatory pathways and enhanced myocardial injury [20]. In fact, a prerequisite for neutrophil-mediated tissue damage is the “priming” effect of various pro-inflammatory stimuli generated by dam-aged tissue during MIR, such as HSP60 and HMGB1 [21]. Cytokines released by TLR-activated cells such as tumor necrosis factor-alpha (TNF-) and IL-1 can elicit neutrophil polarization and upregulation of cell-surface glycoproteins such as macrophage adhesion molecule-1 (Mac-1) [22]; Mac- 1 upregulation in peripheral neutrophils is a very early event in MIR [23].

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2.3. Apoptosis and Mitochondrial Function.

MIR leads to the activation of cell death programs, including apoptosis, autophagy-associated cell death, and necrosis [24]. Apoptosis involves an orchestrated caspase signaling cascade, including caspase-3 and caspase-9, which induces a self-contained program of cell death, characterized by the shrinkage of the cell and its nucleus, with plasma membrane integrity persisting until late in the process [25]. The balance between apoptotic factors Bcl-2 and Bax has been found altered in cardiomyocytes during ischemia [26]. Autophagy is stimulated by nutrient starvation and growth factor deprivation when cells are unable to take up external nutrients. Autophagy is also activated by decreases in ATP in order for the cell to maintain energy homeostasis and survival. Autophagy may serve primarily to maintain energy production during acute ischemia but switch to clear up damaged organelles during chronic ischemia of reperfusion [27]. Multiple cell signaling pathways, such as the AMPK, JNK, and NF-𝜅B pathways, have been shown to be involved in MIR-induced cardiomyocyte apoptosis (Figure 1). AMPK orchestrates the regulation of energy-generating and energy-consuming pathways; its activation has been shown to protect the heart against ischemic injury [28, 29]. Activated JNK signaling, especially in mitochondria, is associated with oxidative stress, mitochondrial dysfunction, and cell death [30]; it is a key modulation event in cell death mediated by reactive oxygen and nitrogen species [31]. JNK is also required for TNF-𝛼-stimulated ROS production and cytochrome c-mediated cell death; Bcl-2 family members are essential components of this mitochondrial apoptotic machinery. Studies have suggested that blockage of JNK mitochondrial translocation or JNK inhibition prevents ROS production and mitochondrial dysfunction and may be an effective treatment for I/R-induced cardiomyocyte death [32–35]. The nuclear factor kappa B (NF-B) also modulates apoptosis during ischemia and reperfusion [36]. TLR signaling pathway leads to translocation of NF-𝜅B to the nucleus and thus up-regulation of expression of proinflammatory cytokines. However, there is the possibility that crosstalk between the TLR/NF-B and PI3K/Akt signaling pathways and modulation of the crosstalk could protect the myocardium from I/R injury [37]. Within the mitochondria-dependent intrinsic apoptosis pathway, which has an important function in cardiac cell injury under various pathological conditions [38], mitochondrial permeability transition pore (MPTP) opening plays a pivotal role [39]. The event of MPTP opening is affected by various factors including intracellular Ca2+, oxidative radicals, ATP levels, and the levels of Bcl-2 family proteins [40]

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2.4. Bone Marrow Stem Cell Migration.

Bone marrow mesenchymal stem cells (BMSCs) are multipotent cells that secrete angiogenic factors. Injured tissues express specific receptors, such as CXCR4, and/or their ligands including stromal cell-derived factor-1 (SDF-1), to facilitate trafficking, adhesion, and infiltration of BMSCs. During MIR, BMSCs are preferentially attracted to and retained in the ischemic tissue [41, 42]. As a result of the hypoxic microenvironment, these BMSCs produce high levels of vascular endothelial growth factor (VEGF), leading to an increase in vessel density and facilitating myocardial regeneration and remodeling [43, 44] (Figure 1). 2.5. Angiogenesis. Angiogenesis refers to the sprouting, bridging, intussusception, and/or enlargement of capillaries. In the late stage of MI repair, enhancement of blood flow to ischemic myocardium can result from either true angiogenesis or the recruitment of preexisting coronary collaterals [45]. VEGF is an endothelial cell-specific angiogenic factor and also a critical regulator of angiogenesis that stimulates proliferation, migration, and proteolytic activity of endothelial cells [46]. Ischemia or coronary artery occlusion induces myocardial VEGF expression, which leads to an angiogenesis-induced restoration of tissue blood flow and the prevention of further tissue damage (Figure 1). In addition, VEGF is a potent survival factor during physiological and tumor angiogenesis and has been shown to induce the expression of anti-apoptotic proteins in endothelial cells [47, 48].

2.5. Other Factors.

The activation of ATP-sensitive potassium (KATP) channel subunits and ATPase, and calcium (Ca2+)4 Evidence-Based Complementary and Alternative Medicine overload are also involved in MIR (Figure 1). Ischemia-reperfusion may activate some ion channels that do not open under normal physiological conditions. One such channel is the KATP channel, whose activation facilitates potassium ion efflux, hyperpolarization, and action potential repolarization. The resulting shortening of the action potential duration decreases the total influx of sodium and calcium, which alleviates the overloading of intracellular calcium (Ca2+) which in turn weakens myocardial contraction force and reduces myocardial oxygen consumption. Therefore, the opening of KATP channels plays an active role in protecting the heart against MIR injury.

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