Effects and mechanisms of chinese herbal medicine in ameliorating myocardial ischemia-reperfusion injury

Abstract

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.

Figure 1

Effects and mechanisms of Chinese herbal medicine in myocardial ischemia-reperfusion (MIR) injury. During ischemia, oxygen is not available to accept the electrons in the metabolic degradation of substrates, and consequently anaerobic metabolites become important in the preservation of myocardial viability. However, free radicals and reactive oxygen species (ROS) formation is markedly increased in this procedure. Reperfusion also generates high ROS levels which have an adverse impact on specific signal transduction systems, thereby predisposing the heart to further oxidative cell damage. Damaged cell debris, fibrinogen, cytokines, and chemokines will activate the receptors, including TLRs, TNFR, and ILR, in the host inflammatory cells as well as the cardiomyocytes. This sterile inflammatory process leads to the formation of a vicious circle, whereby the cardiomyocyte TLRs, TNFR, and ILR are activated by inflammatory cell-generated ligands. Typically, this has an adverse impact on specific signal transduction systems (e.g., AMPK, JNK, and NF-κB pathways), thereby activating the caspase cascade. Elevated ROS levels also result in intracellular Ca²⁺ overload which adversely affects mitochondrial function by opening the mitochondrial permeability transition pore (MPTP). As a result, the balance between Bax and Bcl is interrupted and the caspase cascade is further activated, leading to apoptotic cell death and myocardial tissue damage. Injured tissue expresses SDF-1, which interacts with its specific receptors (e.g., CXCR4) to facilitate the trafficking, adhesion, and infiltration of bone marrow derived stem cells (BMSCs). BMSCs produce high levels of the endothelial cell-specific angiogenic factor, VEGF, which is a critical regulator of angiogenesis that includes the stimulation of proliferation, migration, and proteolytic activity of endothelial cells and eventually leads to an increase in vessel density and the facilitating of myocardial regeneration and remodeling. During the MIR injury process, there are seven target areas where Chinese herbal medicine can exert protective effects on cardiomyocyte. Examples are as follows: (1) anti-oxidation actions of Palmatine, Forsythoside B, and SiNi Decoction; (2) anti-inflammatory properties of Tanshinone IIA, Schisandrin B, and ShuMai Decoction; (3) anti-apoptosis ability of Salidroside, Tyrosol, and Cardiotonic Pill; (4) protection of mitochondrial function by Herba Cistanches, Cistanche, and Guanxin II; (5) increasing BMSCs migration by Tanshinone IIA and Salvianolic acid B (6) promoting angiogenesis by Radix et Rhizoma Rhodiolae Kirilowii, ShuMai Decoction and TongXinLuo Superfine; and (7) inhibiting Ca²⁺ overload by Astragaloside IV, Lycium barbarum, and Acanthopanax senticosus injection.