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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 1  |  Page : 50-58

Recent advances of traditional chinese medicine in the regulation of myocardial mitochondrial function


Research Center for Traceability and Standardization of TCMs, Jiangsu Key Laboratory of TCM Evaluation and Translation Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China

Date of Submission16-Apr-2020
Date of Acceptance20-Jul-2020
Date of Web Publication24-Mar-2021

Correspondence Address:
Prof. Fang Li
Research Center for Traceability and Standardization of TCMs, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/wjtcm.wjtcm_78_20

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  Abstract 


Cardiovascular disease is a crucial disease threatening human health, and its mortality rate ranks first among Chinese residents. Myocardial mitochondrial dysfunction is the main cause of various heart diseases such as myocardial infarction, myocarditis, hypertrophic cardiomyopathy, and heart failure. In recent years, many studies have confirmed that traditional Chinese medicine (TCM) can be used to improve myocardial mitochondrial function and treat heart disease. The purpose of this review was to analyze the regulatory mechanism of myocardial mitochondrial function by summarizing the effect of TCM on cardiovascular disease.

Keywords: Cardiovascular disease; mitochondrial function; multipathway; multitarget; traditional Chinese medicine


How to cite this article:
Wan SY, Hu JG, Zhang Y, Yu BY, Kou JP, Li F. Recent advances of traditional chinese medicine in the regulation of myocardial mitochondrial function. World J Tradit Chin Med 2022;8:50-8

How to cite this URL:
Wan SY, Hu JG, Zhang Y, Yu BY, Kou JP, Li F. Recent advances of traditional chinese medicine in the regulation of myocardial mitochondrial function. World J Tradit Chin Med [serial online] 2022 [cited 2022 May 18];8:50-8. Available from: https://www.wjtcm.net/text.asp?2022/8/1/50/336840




  Introduction Top


Mitochondria are dynamic organelles that provide over 90% of the energy required by the body and are the main site of energy metabolism. Mitochondrial energy production is related to the balance between mitochondrial fusion and division. An increase in mitochondrial fission leads to a decrease in adenosine triphosphate (ATP) production, and a lack of available energy to cardiomyocytes can cause cardiovascular disease, so mitochondrial dynamics maintain homeostasis of the cardiovascular system.[1] Mitochondria in cardiomyocytes not only preserve the pumping function of the heart through respiratory capacity but also participate in regulating cellular signaling, including the production of reactive oxygen species (ROS), calcium homeostasis, and death.[2] Previous studies have shown that the occurrence of myocardial injury is accompanied by mitochondrial dysfunction, which is reflected in the damage to the mitochondrial membrane, alteration of ion concentration, impairment of the mitochondrial electron transport chain, abnormal oxidative phosphorylation (OXPHOS), energy metabolism disorders, and ROS overproduction.[3] Mitochondrial dysfunction can induce the occurrence of many kinds of heart diseases. In this context, treatment for cardiovascular diseases requires the control of mitochondrial protein quality and the regulation of mitochondrial disorders.[4] Recent research has demonstrated that traditional Chinese medicine (TCM) can improve cardiac function and prevent heart disease by adjusting the mitochondrial function in the myocardium. TCM has protective effects on myocardial mitochondrial function, mainly through its effects on multiple signaling pathways, such as PI3K/Akt, reperfusion injury rescue kinase (RISK), adenosine monophosphate-activated protein kinase (AMPK), transforming growth factor-β (TGF-β)/Smad, JAK2/STAT3, CnA/Drp1, MAPK, and MEF2D/PGC-1α [Figure 1]. Based on the mechanism of myocardial mitochondrial damage regulated by TCM, this review covers the research progress regarding the effect of TCM in regulating myocardial mitochondrial function in the last 4 years to provide clues and references for explaining the characteristics and possible mechanisms of TCM in preventing and treating related heart diseases.
Figure 1: Signaling pathways involved in the regulation of myocardial mitochondrial function by traditional Chinese medicine

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  Regulation of Mitochondrial Function in Myocardial Infarction by traditional Chinese Medicine Top


The heart is the largest oxygen-consuming organ in the human body. In a hypoxic environment, metabolic disorders affect normal cardiac functions, such as blood perfusion.[5] Hypoxia/ischemia may affect the function of the mitochondrial membrane permeability transport pore (mPTP) through oxidative stress, and calcium overload mechanically hurts the mitochondrial outer membrane, resulting in the release of cytochrome C (Cyt C), and initiates apoptosis.[6],[7] Therefore, repairing mitochondrial damage contributes to protecting against hypoxia/ischemia-induced cardiomyocyte injury, which is a strategic point in the prevention and treatment of myocardial infarction (MI). With the popularization of modern medical knowledge and the enhancement of public medical awareness, an increasing number of patients with MI are choosing to receive the percutaneous coronary intervention (PCI), but PCI will undoubtedly result in myocardial ischemia-reperfusion injury (MIRI). MIRI is a more severe pathological injury that occurs when ischemic myocardial tissue restores hemoperfusion. Since mitochondria are the core site of cell energy metabolism, dysfunction is a vital cause of MIRI.[8] Therefore, research on anti-MIRI effects of TCM also tends to focus on the protection of mitochondrial function. QiShenYiQi pills (QSYQ; 0.6 mg/kg) are composed of Radix Astragali, Salvia miltiorrhiza, Panax notoginseng, and rosewood, which could improve MI by improving mitochondrial structure; increasing myocardial ATP content, ATP 5D protein expression, and ATP synthase (ATPase) activity; and inhibiting myocardial energy metabolism disorder.[9] Shenmai (SM; 10 mL/kg; 20 μL/mL) is composed of red ginseng and Radix Ophiopogonis, which could increase mitochondrial maximum respiration, ATP-coupled respiration and spare capacity, and maintain mitochondrial membrane potential (MMP) and ATP concentration in rat myocardial ischemia and primary cardiomyocytes hypoxia models. SM also played a role in resisting ischemia hypoxia-induced cardiomyocyte damage.[10] Shenmai injection (SMI; 0.38 mL/kg; 1 μL/mL) attenuated MIRI by decreasing the content of cytosolic Ca2+, maintaining MMP, and inhibiting the mPTP openness and mitochondria fission excessively to maintain the integrity of myocardial mitochondria in an MI rat model and hypoxia-reoxygenation (H/R)-induced H9c2 cell model.[11] YiQiFuMai powder (YQFM; 1.06 g/kg; 400 μg/mL), which is composed of ginseng Radix Et Rhizoma Rubra, Ophiopogonis Radix, and Schisandrae Chinensis Fructus, and the combination of three compounds from Shengmai preparations (GRS; 6.4–19.2. mg/kg; 0.1–10 μg/mL), which include ginsenosides Rb1, ruscogenin, and schisandrin, inhibited cardiomyocyte apoptosis by activating the AMPK pathway and maintaining MMP and ATP content of cardiomyocytes in MIRI mice and an H/R-induced H9c2 cell model.[12],[13] The Suxiao Jiuxin pill (SX; 100 μg/mL) mainly consists of tetramethylpyrazine and borneol, which could reduce the mRNA expression of adenylate cyclase (Adcy) 1, Adcy2, Adcy3, Adcy6, and Adcy8 and increase the mRNA expression of CytC oxidase subunit 6a2 (Co × 6a2), glycogen synthase kinase 3β (GSK3β), and phosphatidylinositol kinase-3 catalytic subunit α (Pik3ca) to maintain MMP, thereby inhibiting hypoxia-induced apoptosis of the HL-1 cardiomyocyte.[14],[15] Gypenosides (GP; 50–200 mg/kg) and total salvianolic acid injection (TSI; 8 mg/kg; 0.013 mg/mL) consist of a preparation of active components of S. miltiorrhiza Bunge. Xinshuitong capsule (XST; 200–600 μg/mL) consists of Astragali Radix, Pseudostellariae Radix, and S. miltiorrhizae Radix, which might improve MIRI by repairing the activity of mitochondrial respiratory chain complexes, increasing ATP levels in cardiomyocytes, maintaining the integrity of mitochondrial membranes, and inhibiting the release of CytC.[16],[17],[18] Moreover, Yixin-Shu (YXS; 60, 120 mg/kg) contains S. miltiorrhiza, Astragalus membranaceus, Ligusticum wallichii, and Fructus Crataegi, which alleviated MIRI effectively by inhibiting mitochondrial swelling, upregulating the expression of endogenous nuclear receptor liver x receptor α, and inhibiting mitochondria-mediated apoptosis and oxidative stress.[19] In addition, ginsenoside Rb1 (100 μmol/L; 6.25–100 μmol/L), ginsenoside Rg5 (10 μmol/L), shikonin (10–40 μmol/L), and apigenin (1–25 μmol/L) could activate the Akt/GSK3β, PI3K/Akt, PI3K/Akt/GSK3β, and Akt/HK-II/Drp1 signaling pathways; reduce intracellular ROS generation; and maintain MMP and the integrity of myocardial mitochondrial membranes to ameliorate MIRI.[20],[21],[22],[23] Ginsenoside Rg1 (12.5 μmol/L) prevented H/R-induced cardiomyocyte damage by avoiding mitochondrial dynamic imbalance through regulating glutamate dehydrogenase, increasing mitochondrial length, and reducing mitochondrial fragmentation.[24] Ginseng polysaccharides (50 and 200 mg/mL) alleviated H/R-induced cardiomyocyte apoptosis through activating RISK and endothelial nitric oxide synthase pathways, maintaining MMP, inhibiting CytC release, and increasing ATP content and oxygen consumption rate (OCR).[25] Danshensu (10 μmol/L) downregulated mRNA expression of the c-subunit of ATPase, inhibiting mPTP openness and cardiomyocyte apoptosis in MIRI model rats.[26] Polydatin (PD; 5–10 mg/kg; 1–100 μmol/L) inhibited cardiomyocytes apoptosis through promoting autophagy, maintaining MMP, and limiting ROS generation in MIRI mouse and primary cardiomyocyte H/R models.[27] Furthermore, scutellarin (25–100 μmol/L) could inhibit H/R-induced oxidative stress and apoptosis by maintaining myocardial MMP, improving cell proliferation and the activity of superoxide dismutase (SOD), and promoting JAK2/STAT3 activation and the expression of VEGF, MMP2, and MMP9.[28] Luteoloside (20 μmol/L) and myricitrin (10–40 μmol/L) suppressed H/R-induced cardiomyocyte apoptosis by increasing the expression of the levels of highly glycosylated phosphoserine agglutinin protein η (14-3-3η) and heat shock protein 90 (Hsp90), respectively, inhibiting ROS generation and mPTP openness, and maintaining MMP.[29],[30] The pathogenesis of MIRI is very complicated. Previous studies have shown that oxidative stress and subsequent myocardial apoptosis are the important pathomechanisms in the occurrence and development of MIRI.[31],[32] Hence, many scholars applied H2O2-induced damage to simulate oxidation stress injury in MIRI. Icariin (1–10 μmol/L) could maintain the balance of MMP and calcium ions (Ca2+), inhibit ROS generation, and thereby alleviate H9c2 cardiomyocyte injury induced by H2O2.[33] Dendrobium officinale polysaccharide (6.25–25 μg/mL) could inhibit H2O2-induced H9c2 cardiomyocyte apoptosis by reducing lipid peroxidation damage, increasing endogenous antioxidant activity, inhibiting ROS generation, and maintaining MMP, which was associated with the PI3K/Akt and MAPK signaling pathways.[34]


  Regulation of Mitochondrial Function in Myocarditis by Traditional Chinese Medicine Top


Myocarditis is a kind of myocardial inflammatory disease caused by infection, physics, and chemistry and can be caused by the clinical use of drugs such as antibiotics and tumor chemotherapy drugs, which can directly lead to myocardial cell damage. Studies have shown that the mechanism of myocardial injury induced by doxorubicin (DOX), a representative anthracycline antitumor drug, is generally considered to be related to ROS increase, mitochondrial damage, and apoptosis in cardiomyocytes.[35] Regulating myocardial mitochondrial function to alleviate myocarditis may be one of the essential uses of TCM. Sanyang Xuedai mixture (SYKT; 30 mg/mL) comprises Daemonorops draco, P. notoginseng, Scoparia dulcis, Aralia cordata, Alpinia officinarum, Dioscorea opposita, Wolfiporia extensa, and Amomum villosum, which could retard DOX-induced cardiomyocyte apoptosis by maintaining MMP, reducing the expression of CytC and poly ADP-ribose polymerase, and inhibiting the activation of the p53 and p38/JNK signaling pathways.[36] Ginsenoside Rg3 (10 mg/kg) attenuated the DOX-induced cardiotoxicity through inhibiting ROS generation, increasing ATP content, maintaining MMP, and reducing Ca2+ overload in mitochondria.[37] Honokiol (0.2 mg/kg) could protect the heart from DOX-induced myocardial damage by enhancing myocardial mitochondrial respiration, increasing PPARγ expression, and inhibiting mitochondrial protein acetylation.[38] Danshensu-tetramethylpyrazine conjugate (DT-018) (3–100 μmol/L) could reduce intracellular and mitochondrial ROS production, restore intracellular ATP levels, maintain MMP, inhibit mitochondrial swelling, and activate the MEF2D/PGC-1α pathway, thereby improving H9c2 cell injury induced by t-BHP.[39] Salvianolic acid A (Sal A; 10 μmol/L) protected the heart from arsenic trioxide-induced damage by increasing PGC-1α expression and maintaining normal division and fusion of mitochondria.[40] Cydonia Oblonga Mill (ACO; 50, 100 μg/mL) and Ficus carica L (AFC; 100, 200 μg/mL) could alleviate DOX-induced myocardial damage by inhibiting ROS generation, membrane lipid peroxidation, mitochondrial swelling, and Cyt C release; maintaining MMP; and reducing GSH levels and SDH activity.[41]


  Regulation of Mitochondrial Function in Hypertrophic Cardiomyopathy by Traditional Chinese Medicine Top


Hypertrophic cardiomyopathy (HCM) is a kind of heart disease characterized by myocardial hypertrophy. Continuous myocardial hypertrophy can gradually develop into heart failure (HF). Ischemia, hypoxia, and hypertension are the main pathogenic factors of HCM. Various investigations have shown that the pathogenesis of HCM is closely linked with mitochondrial dysfunction.[42] Therefore, improving mitochondrial dysfunction might be a significant strategy for treating HCM and preventing the occurrence of HF. Shensong Yangxin Capsule (SSYX; 0.25–1 μg/mL) is composed of Panax ginseng, S. miltiorrhiza, and Nardostachys jatamansi, which could improve fatty acid metabolism and glucose metabolism by increasing myocardial mitochondrial density during cardiac hypertrophy and mRNA and protein expression levels of PGC-1α, p-AMPK, CPT-1, and GLUT-4 in angiotensin II (AngII)-induced primary cardiomyocyte injury models.[43] Qiliqiangxin (QLQX; 1 g/kg) is composed of Astragali Radix, ginseng radix et rhizoma, and aconiti lateralis radix preparata, which prevented the occurrence of hypertension-induced cardiac remodeling through improving mitochondrial ultrastructural damage and increasing the expression levels of PPAR-α, PPAR-γ, and PGC-1α in a rat model of primary hypertension.[44] Shengmai San (SMS; 3, 4.5 g/kg) is a compound medication including P. ginseng, Ophiopogon japonicus, and Schisandra chinensis, which could alleviate myocardial hypertrophy and diastolic dysfunction in diabetic cardiomyopathy by ameliorating myocardial mitochondrial ultrastructure, increasing the activity of the OXPHOS complex and cellular ATP level, maintaining MMP, and activating SIRT1/AMPK/PGC-1α and mitochondrial uncoupling pathways to improve mitochondrial lipid metabolism in a leptin receptor-deletion db/db mice model.[45]


  Regulation of Mitochondrial Function in Heart Failure by Traditional Chinese Medicine Top


Myocardial mitochondrial dysfunction during HF is a continuous and dynamic process, which is the result of multiple factors, numerous mechanisms, and vicious cycles. TCM provides protective effects for myocardial mitochondria during HF with the advantages of multiple targets and pathways, and overall regulation, which provides ideas and references for studying the pathogenesis and targeted treatment of HF. Qishenkeli (QSKL; 2.33 g/kg) prepared from a basic formula (Radix Astragali, Mongolici, S. miltiorrhiza Bunge, Flos Lonicerae, Scrophularia, Radix Aconiti Lateralis Preparata, and Radix Glycyrrhizae) alleviated left anterior descending coronary artery (LADCA) ligation-induced HF through suppressing intracellular ROS generation, maintaining MMP, regulating the p53/PI3K/Akt pathways, and inhibiting cardiac myocyte apoptosis.[46] Extracts of SMS (ESMS; 45.5–728 mg/kg; 400 μg/mL) increased ATPase activity, reduced intracellular Ca2 + levels, and maintained MMP and cellular ATP content, thereby inhibiting the CnA/Drp1-mediated mitochondrial apoptotic pathway to attenuate ischemia-induced HF in a mouse and H9c2 cell hypoxia model.[47] YQFM (130–530 mg/kg; 800 μg/mL) improved LADCA ligation-induced HF by increasing the expression of Mitofusin2; maintaining MMP by reducing expression of NOX2, NOX4, and ROS generation; downregulating the expression of calcium voltage-gated channel subunit α1C; and then inhibiting the CaMKII pathway.[48] Yiqi Huoxue decoction (YQHX; 8.2 g/kg) is composed of A. membranaceus, Angelica sinensis, P. ginseng, L. wallichii, and P. notoginseng, which could protect myocardial cells during HF by increasing the expression of Tfam and NRF-1, activating the AMPK/PGC-1α pathway, improving the mitochondrial ultrastructure, and maintaining MMP.[49] The combination of Aconiti Lateralis Radix Praeparata (Fuzi) and Zingiberis Rhizoma (Ganjiang) improved acute HF induced by propafenone hydrochloride through increasing cardiac MRCC, mitochondrial Ca2+ uniporter (MCU) complex, MICU1-2 expression levels, dehydrogenase (ADH), malate dehydrogenase, and nicotinamide nucleotide transhydrogenase activity.[50] In addition, ginsenoside Rb1 (35, 70 mg/kg) increased the translocation of GLUT4 to the plasma membrane by maintaining MMP, which was mainly achieved through the regulation of the TGF-β1/Smad, ERK, and Akt pathways, and subsequently prevented the occurrence of HF induced by abdominal aortic coarctation.[51] Astragaloside IV (0.3–1 mg/kg) alleviated the HF induced by transverse aortic constriction by activating the PLB/SERCA2a/PPARα pathways, promoting fatty acid β oxidation, increasing ATP content, reducing anaerobic glycolysis, and increasing the oxygen consumption ratio.[52]

Others

Kudiezi (KDZ; 22.65 mL/kg) is extracted from the Chinese herb Ixeris, which could alleviate myocardial injury induced by acute cerebral ischemia through enhancing GSH and SOD levels and increasing activation of COX and mRNA expression of COX I and COX III in myocardial mitochondria.[53] Resveratrol (12.5 μmol/L) inhibited the PINK1/Parkin pathway and increased Drp1 expression, ameliorated mitochondrial elongation, decreased mitochondrial content, and then prevented the occurrence of d-galactose-induced senescent-like cardiomyocytes.[54] Luteolin (7.5–30 μmol/L) could improve hypothermia-induced myocardial injury by reducing calcium overload, inhibiting circulation of calcium and accumulation of calmodulin in cardiomyocytes, restraining activation of protein kinase A, and increasing the activation of Ca2+-Mg2+-ATPase.[55]

Summary and prospect

As important organelles of cardiomyocytes, mitochondria can not only provide energy to cardiomyocytes through OXPHOS but also participate in maintaining calcium ion homeostasis, signal transduction, apoptosis, synthesis, and catabolism of molecules.[56],[57] Studies have shown that the investigation of myocardial mitochondrial protection pathways is helpful to further reveal the pathological mechanism of myocardial structure and dysfunction, which has vital significance for improving the cardiac function of injured myocardium and preventing the occurrence of cardiovascular diseases.[58] The specific classification, experimental model, evaluation index, and action pathway of studies on the regulation of myocardial mitochondrial function by TCM are summarized in [Table 1]. The TCM with myocardial mitochondrial function-regulating activity involves active ingredients, extracts, and compound prescriptions corresponding to 22, 2, and 19 pieces of literature, respectively. These studies include the current reports and in-depth studies on the regulation of myocardial mitochondrial function by TCM based on the active ingredients of TCM. Saponins have a wide range of action pathways, and they have protective effects on myocardial mitochondrial function involved in the improvement of mitochondrial membrane damage, mitochondrial dynamic imbalance, mitochondrial Ca2 + overload, glucose, and fatty acid oxidation. In addition, it is believed that medicines of “tonifying qi” can benefit qi and promote blood circulation converging to sores and muscles, improve heart function, and protect the myocardium. The active ingredients and compound preparations of TCM with “tonifying qi” that have a protective effect on mitochondrial function have been frequently reported, and most of them have been used to treat cardiovascular diseases. The TCM theory believes that “qi” is the necessary material basis to maintain normal physiological functions of the human body. At the same time, many components of “tonifying qi” in TCM have the potential function to correct energy metabolism, and mitochondria are the primary site of metabolism. Therefore, the theory of “tonifying qi” is mostly associated with improving mitochondrial dysfunction.[59] Furthermore, mitochondria are dynamic organelles with relatively complex structures, and the pathological mechanisms of heart diseases are very complicated. Therefore, TCM may have more advantageous features regarding the regulation of myocardial mitochondria in heart diseases, with multiple components, targets, and pathways to exert their pharmacological effects. Modern research technologies and the basic theories of TCM need to be further explored in the future. Above all, with the continuous elucidation of the pathological mechanisms of heart disease, studies on the mechanisms of TCM to improve myocardial injury are deepening, and the research on regulating myocardial mitochondria has also progressed. Further elucidating the mechanism of TCM and discovering its key targets or interaction network for regulating myocardial mitochondrial function will provide possible therapeutic strategies for preventing and treating related heart diseases.
Table 1: A summary of the regulation of myocardial mitochondrial function by traditional Chinese medicine

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Acknowledgments

This research work was supported by the National Natural Science Foundation of China (No. 81973506, No. 81603328, No. 81774150, No. 81573719), Natural Science Foundation of Jiangsu Province (BK20160761), Project funded by China Postdoctoral Science Foundation (2016M600456, 2017T100425), and supported by “Double First-Class” University project (CPU2018GF06, CPU2018GF07).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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