Promising Therapeutic Candidate for Myocardial Ischemia/Reperfusion Injury: What Are the Possible Mechanisms and Roles of Phytochemicals?

Abstract

Percutaneous coronary intervention (PCI) is one of the most effective reperfusion strategies for acute myocardial infarction (AMI) despite myocardial ischemia/reperfusion (I/R) injury, causing one of the causes of most cardiomyocyte injuries and deaths. The pathological processes of myocardial I/R injury include apoptosis, autophagy, and irreversible cell death caused by calcium overload, oxidative stress, and inflammation. Eventually, myocardial I/R injury causes a spike of further cardiomyocyte injury that contributes to final infarct size (IS) and bound with hospitalization of heart failure as well as all-cause mortality within the following 12 months. Therefore, the addition of adjuvant intervention to improve myocardial salvage and cardiac function calls for further investigation. Phytochemicals are non-nutritive bioactive secondary compounds abundantly found in Chinese herbal medicine. Great effort has been put into phytochemicals because they are often in line with the expectations to improve myocardial I/R injury without compromising the clinical efficacy or to even produce synergy. We summarized the previous efforts, briefly outlined the mechanism of myocardial I/R injury, and focused on exploring the cardioprotective effects and potential mechanisms of all phytochemical types that have been investigated under myocardial I/R injury. Phytochemicals deserve to be utilized as promising therapeutic candidates for further development and research on combating myocardial I/R injury. Nevertheless, more studies are needed to provide a better understanding of the mechanism of myocardial I/R injury treatment using phytochemicals and possible side effects associated with this approach.

Keywords: mechanisms; myocardial ischemia/reperfusion injury; pharmacology; phytochemicals; therapeutic implication.

Figure 1

A simplified scheme of the mechanism of acute myocardial I/R injury. During acute myocardial ischemia, ischemic cardiomyocytes switch to anaerobic metabolism to provide ATP. However, this results in the Na+-H+ exchanger to extrude H+ and results in intracellular Na+ overload, which activates the 2Na+-Ca2+ exchanger to function in reverse to extrude Na+ and leads to intracellular Ca2+ overload. The endoplasmic reticulum also markedly reduces Ca2+ reuptake, which exacerbates intracellular Ca2+ overload. Ca2+ can also induce MPTP opening. During reperfusion, the influx of oxygen fuels production of ROS (oxygen paradox). Other sources of ROS include xanthine oxidase (endothelial cells) and NADPH oxidase (neutrophils). ROS can damage virtually every biomolecule found in cells, promote the opening of mPTPs, and activate inflammatory and thrombogenic cascades to exacerbate cell injury.

Figure 2

The simplified mechanism scheme of phytochemicals in cardiovascular disease. Phytochemicals reduce the phosphorylation of STAT3 by inhibiting JAK2, which is activated following the binding of cytokines and cognate receptors. Inhibition of the JAK/STAT pathway leads to decreasing of iNOS and NLRP3/IL-1β levels, and thus protects against oxidative stress and inflammation. Activation of the AMPK signaling pathway may also play a key role in the anti-inflammation, further acting on the mTOR and Nrf2 factors and participating in the actions of phytochemicals on oxidative stress, apoptosis, and autophagy. Moreover, the NF-κB signaling pathway, activated by the BRCA1, JNK, and AKT, promotes the expression of TNF-α and IL-6, which regulate inflammation and apoptosis. The phytochemicals are also against apoptosis and inhibit Ca2+ accumulation via the STIM1 pathway. The PI3K-AKT signaling pathway is activated by many types of cellular stimuli or toxic insults, activates downstream mTOR, eNOS, and NF-κB, and sequentially regulates the inflammation and apoptosis.