Modulatory Effects Of Chinese Herbal Medicines On Energy Metabolism in Ischemic Heart Diseases-Ⅰ

INTRODUCTION 

Ischemic heart disease (IHD) is the most common cause of death among cardiovascular diseases, which imposes a substantial social and economic burden. The Global Burden of Disease Study of 2017 (GBD 2017) has reported that the total number of deaths from IHD increased from 7.30 to 8.93 million between 2007 and 2017 at a global level (GBD 2017 Causes of Death Collaborators, 2018). IHD is comprised principally of coronary heart disease (including angina, nonfatal myocardial infarction, and coronary death), asymptomatic myocardial ischemia, sudden cardiac death, and ischemic heart failure (Wong, 2014; Guo et al., 2018). Current therapeutic approaches are mainly dependent on medical interventions such as statins, antiplatelet drugs, beta-receptor blockers (b-blockers), and angiotensin-converting-enzyme inhibitors (ACEIs), in addition to surgical procedures such as percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery. Although these medical and surgical therapies have proven effective in reducing morbidity and mortality after IHD, millions of patients still have clinical symptoms, including chest tightness, heart palpitations, shortness of breath, and fatigue. Therefore, developing novel treatment strategies involving different mechanisms in myocardial ischemia and even reperfusion is crucial.

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Cardiac energy metabolism plays a major role in the progression of cardiovascular diseases. Van Bilsen et al. (2004) proposed the concept of myocardial metabolic remodeling. With the development of modern science and advanced technologies, alterations in myocardial energetics such as shifts in energy substrate utilization, impaired mitochondrial oxidative phosphorylation, and reduction in the adenosine triphosphate (ATP) transfer and utilization capacity are increasingly recognized as playing a crucial role in the mechanisms of IHD (Fukushima et al.,2015; Tuomainen and Tavi, 2017). Deprivation of cardiac energy leads to cardiac contractile dysfunction, left ventricular remodeling, and even heart failure (HF). Consequently, growing evidence supports that modulation of cardiac energy metabolism can be an effective means of improving cardiac function and slowing the progression to HF (Neubauer, 2007; Lang et al., 2015; Qi and Young, 2015; Yang et al., 2016; Tuomainen and Tavi, 2017). Chinese herbal medicines (CHMs) have drawn much attention recently as a potential therapeutic strategy for the prevention and treatment of myocardial ischemia through modulating energy metabolism. It is a novel strategy for protecting the ischemic myocardium against IHD. This review focuses on the potential efficacy of herbs, major bioactive components (MBC), and Chinese herbal formulas (CHF) in modulating cardiac energy metabolism in IHD and the associated mechanisms.

TARGETS AND SIGNALING OF CARDIAC ENERGY METABOLISM FOR CHINESE HERBAL MEDICINES 

"Qi-blood" Theory of TCM Is Connected With Cardiac Energy Metabolism 

The healthy adult heart has perpetually high energy demands and needs to contract to supply the body with blood and oxygen continuously. As powerhouses of cardiomyocytes, mitochondria are continuously supplying the energy required for cardiac muscle contraction. Under normal conditions, almost of ATP generation in the healthy adult heart comes from mitochondrial oxidative phosphorylation, with the rest mainly derived from glycolysis. In an ischemic heart, impaired mitochondrial oxidative phosphorylation provides an insufficient supply of ATP to cardiomyocytes. The available evidence suggests that cardiac energy metabolism is in good correlation with cardiac function. Reduced capacity for cardiac energy transduction leads to cardiac pump dysfunction, blood flow disturbance, cardiac contractile dysfunction, and even heart failure (Huss and Kelly, 2005). The search for treatment strategies for modulating cardiac energy metabolism is one of the major challenges in cardiovascular diseases.

Traditional Chinese medicine (TCM) is characterized by a "Holistic concept" that the organism is considered as a whole. In TCM, Qi and blood are the essential substances of organisms, which maintain the life activity of humans. Qi has promoting, warming, consolidation, and retention functions, which provide energy for promoting blood circulation and keeping the blood flowing within the vessels. As the first Chinese medical classic and the origin of TCM theory, the Suwen of Yellow Emperor's Internal Classic describes the heart governing blood and vessels. It means that Heart-Qi promotes and keeps the formation and circulation of blood in the vessels for nourishing the organs and tissues, retaining body fluid balance, and maintaining normal physiological activities. An abundance of the Heart-qui, a sufficiency of blood, and vascular patency are three principal components that control the normal circulation of blood. In the heart, Heart-Qi drives ATP synthesis via ATP synthase in the cardiac mitochondria to provide the vital energy necessary for cardiac muscle contraction and relaxation. Symptoms of myocardial ischemia in clinical patients mainly include chest tightness, heart palpitations, shortness of breath, and weakness. These symptoms of myocardial ischemia correspond to the symptoms of Heart Qi deficiency syndrome, which further causes blood circulation disorder and cardiac microcirculatory disturbance leading to blood stasis syndrome. Deficiency of Heart Qi can also cause insufficiency of the HeartYang, which is accompanied by a series of symptoms such as cold sweat, and intolerance to cold and cold limbs. Moreover, Heart Qi deficiency can induce microvascular hyperpermeability, leading to excessive fluid, phlegm, edema, and hemorrhage. Based on the "Qi-blood" theory of TCM, Chinese herbal medicines that can tonify or regulate Qi and activate blood have promise as an important therapeutic approach to the modulation of cardiac energy metabolism in cardiology.

The Possible Targets of Cardiac Energy Metabolism for Chinese Herbal Medicines 

Chinese herbal medicines, such as natural botanical herbs, have a long history of clinical use in the treatment of cardiovascular diseases and have properties of numerous potential pharmacological targets. They hold great and unique potential in the management of cardiac energy metabolism, especially in the aspects of mitochondrial function, lipid metabolism, and glucose metabolism. Some of these possible targets are described below, categorized by the process of cardiac energy metabolism. The metabolic process involved in cardiac energy metabolism consists of three main components (Figure 1), namely, energy substrate preference, mitochondrial oxidative phosphorylation, and ATP transfer and utilization (Neubauer, 2007).

Energy substrate utilization represents the first component. Cardiomyocytes can metabolize all classes of energy substrates, including fatty acids, glucose, glycogen, lactate, ketone bodies, and certain amino acids (Heggermont et al., 2016). Free fatty acids (FFA) and glucose first enter the myocardium from the plasma and are then converted respectively to fatty acyl-coenzyme A (acyl-CoA) and glycolytic end product pyruvate in the cytoplasm of cardiomyocytes. Long-chain fatty acyl-CoA is transported into mitochondria via carnitine palmitoyl transferase 1 and 2 (CPT1 and CPT2), whereas pyruvate is taken up into mitochondria by the mitochondrial pyruvate carrier (MPC) (Arumugam et al., 2016; Noordali et al., 2018).

The second component is mitochondrial oxidative phosphorylation, which supplies more than 95% of the ATP required by the mature heart. Normally, fatty acid beta-oxidation (FAO), the major source of mitochondrial oxidative phosphorylation, provides more than two-thirds of the energy demands in adult myocardium, with the remainder being provided by the oxidation of substrates such as carbohydrates, lactate, ketone bodies, and several amino acids (Heggermont et al., 2016). These mitochondrial substrate fluxes via specific metabolic steps (especially fatty acid beta-oxidation and pyruvate oxidation) yield acetyl coenzyme A (acetyl-CoA), which subsequently enters the tricarboxylic acid (TCA) cycle (Kolwicz et al., 2013). Nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) are generated by the TCA cycle and beta-oxidation, respectively (Schwarz et al., 2014). NADH and FADH2 feed high-energy electrons into the mitochondrial electron transport chain (ETC), generating an electrochemical gradient through ETC complexes (complex I-V) across the inner mitochondrial membrane (IMM) that subsequently drives ATP synthesis (Huss and Kelly, 2005). Among them, ATP synthase (complex V), as the final step of mitochondrial oxidative phosphorylation, generates ATP by phosphorylating adenosine diphosphate (ADP). The transfer of electrons between complexes is mediated by ubiquinone (CoQ) and cytochrome c (cyt c). As well as generating NADH and FADH2, the TCA cycle also produces excess citrate in the cytosol, where it is converted into acetyl CoA (Murphy et al., 2016; Noordali et al., 2018). Cytosolic acetyl CoA is further converted into malonyl CoA via acetyl CoA carboxylase (ACC), whereas malonyl CoA, a potent inhibitor CPT-1, can be converted back into acetyl CoA via malonyl CoA decarboxylase (MCD), thereby regulating the entry of FFA into the mitochondria once again (Fukushima et al., 2015; Noordali et al., 2018). The third component comprises cardiac ATP transfer and utilization via the creatine kinase (CK) system (Neubauer, 2007; Fukushima et al., 2015). High-energy phosphates are transferred from the ATP generated via oxidative phosphorylation in the mitochondria to creatine (Cr), thus forming phosphocreatine (PCr) and ADP by the action of mitochondrial creatine kinase. Phosphocreatine rapidly diffuses from the mitochondria into the myofibrils and then reforms ATP and Cr via the action of myofibrillar creatine kinase (Neubauer, 2007). Subsequently, ATP is used by myosin ATPase to produce the force of cardiac contraction, while the free Cr diffuses back to the mitochondria.

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The Possible Transcriptional Signaling of Cardiac Energy Metabolism for Chinese Herbal Medicines 

The mechanisms of cardiac energy metabolism are complex and are primarily controlled by metabolic proteins (enzymes and transcriptional components) that regulate the expression of a large number of genes involved in myocardial energy metabolism through multiple metabolic pathways (Stanley et al., 2005). In particular, mitochondrial structure and function are regulated by numerous genes, including the 37 encoded in mitochondrial DNA and a considerable number encoded in nuclear DNA (Ham and Raju, 2016). It is becoming increasingly clear that multiple nuclear-mitochondrial crosstalk and signaling pathways play an important role in regulating cardiac energy metabolism under ischemic conditions (Qi and Young, 2015; Murphy et al., 2016).

Chinese Herbal Medicines can also modulate numerous potential pathways because of their properties of multicomponent. Some of these possible pathways are described below (Figure 2). Adenosine monophosphate-activated protein kinase (AMPK) is a critical intracellular energy sensor, and its activation is involved in multiple signaling pathways, including modulating glucose and fatty acid metabolism, mitochondrial function, and autophagy (Murphy et al., 2016; Nishida and Otsu, 2016). AMPK consists of three protein subunits: a catalytic subunit, containing the Thr172 site that must be phosphorylated for AMPK activation, and two regulatory subunits (g and b) (Zaha and Young, 2012). The AMPK activity is partly activated by an increase in the AMP/ATP ratio in low-energy states. During myocardial ischemia, the activity of AMPK in the myocardium is activated as an adaptive response to cardiomyocyte stress, leading to a series of changes in metabolic pathways. Activation of AMPK increases cellular glucose uptake by mediating the transport of the glucose transporter 4 (GLUT4) from the cytosol to the sarcolemma membrane in ischemia at an early adaptive stage (Russell et al., 2004; Qi and Young, 2015), and promotes glycolysis through phosphofructokinase 2 (PFK2) phosphorylation (Marsin et al., 2000). AMPK can inhibit the activity of glycogen synthase (GS), which indirectly promotes glycogen utilization (Qi and Young, 2015). Moreover, AMPK also plays a critical role in modulating lipid metabolism. Activated AMPK facilitates the myocardial uptake of fatty acids by promoting the translocation of the fatty acid transporter CD36 (Luiken et al., 2003). Meanwhile, the Activation of AMPK further results in a decrease of malonyl-CoA levels via inactivation of ACC, which effectively promotes fatty acid oxidation by relieving CPT-1 suppression (Dyck and Lopaschuk, 2006) (Figure 1). Meanwhile, the process of mitochondrial biogenesis keeps in a dynamic balance, which undergoes constant fusion and fission. Dynamin-related protein 1 (Drp1) and Fission 1 (Fis1) are known to promote mitochondrial fission. Mitofusin 1 and 2 (MFN1 and MFN2) mainly mediate outer 

membrane fusion, whereas Opa1 is mainly responsible for inner membrane fusion. Mitochondrial dynamics imbalance leads to defects in mitochondrial morphology and mitochondrial dysfunction during ischemic contexts. Hypoxia-induced AMPK activation can promote mitochondrial fission via the phosphorylation of mitochondrial fission factor (MFF), which is considered to be a mitochondrial outer membrane receptor for Drp1, an essential enzyme for providing a driving force in mitochondrial fission (Garcia and Shaw, 2017). Besides, autophagy is regulated by AMPK activation, which restores impaired myocardial function via the mechanistic target of rapamycin (mTOR) (Wu et al., 2020a).

Peroxisome proliferator-activated receptor gamma (PPARg) coactivator (PGC-1a) is a well-characterized mediator of mitochondrial biogenesis and respiratory, and its activity can also be modulated by AMPK phosphorylation (Gundewar et al., 2009) (Figure 2). In addition to AMPK phosphorylation, PGC- 1aactivity is tightly controlled by the NAD+ -dependent deacetylase sirtuin-1 (SIRT1) deacetylation, which promotes mitochondrial biogenesis (Fernandez-Marcos and Auwerx, 2011; Zaha and Young, 2012; Ham and Raju, 2016). As a cofactor, PGC-1a is known to control the expression of multiple nuclear receptors and transcription factors, thereby regulating the entire metabolic phenotype of cardiomyocytes. PGC-1a modulates mitochondrial biogenesis and oxidative phosphorylation by directly activating nuclear respiratory factors (NRF1 and NRF2) and the estrogen-related receptor alpha (ERRa) transcription factor. NRF1 activates the downstream synthesis of mitochondrial transcription factor A (mtTFA), which regulates mtDNA replication, transcription, and maintenance (Kang and Hamasaki, 2005; Rowe et al., 2010). As a major transcriptional partner of PGC-1a, ERRa can induce an increase in the expression of NRF2, modulating cardiomyocyte cycle and differentiation, and mitochondrial biogenesis (Ham and Raju, 2016). PGC-1a also co-activates PPARa, which is involved in fatty acid metabolism in cardiomyocytes (Finck, 2007; Lehman et al., 2000). Furthermore, PGC-1a activation enhances mitochondrial respiration by increasing the expression of cytochrome c, cytochrome c oxidase subunits II and IV (COX II and IV), and ATP synthase (Choi et al., 2008; Espinoza et al., 2010).

MODULATORY EFFECTS OF CHINESE HERBAL MEDICINES ON ENERGY METABOLISM IN IHD 

Cardiac energy metabolism is highly flexible concerning energy substrates, with a dynamic balance that is modified by aging, as well as physiological and pathological contexts (Huss and Kelly, 2005; Arumugam et al., 2016). Increased fatty acid beta-oxidation with aging is accompanied by a progressive decrease in glycolytic metabolism. The fetal heart uses glucose oxidation as a major source of energy, while the adult myocardium is considerably more dependent on fatty acid metabolism. Interestingly, during ischemic conditions, the cardiac metabolic profile shows significant similarities with that of the fetus. This phenomenon is considered to revert to the "fetal phase" (Tuomainen and Tavi, 2017). In addition to shifts in cardiac substrate utilization, alterations in mitochondrial ultrastructural and function play a crucial role in the mechanisms of IHD. Cardiac mitochondria, as the powerhouses of the cardiomyocytes, involve a complex series of processes of oxidative phosphorylation. They are not only a primary source of ATP synthesis and reactive oxygen species (ROS) production in cardiac myocytes but also play a critical role in the process of apoptosis. Myocardial hypoxia/ischemia inhibits a series of processes of mitochondrial oxidative phosphorylation and diverts the pyruvate to lactate leading to cellular acidification. The ischemic cardiomyocyte shows a marked reduced ability to synthesize ATP, a significantly increased mitochondrial ROS production, calcium influx, and even Ca2+ overload leading to mitochondrial membrane permeability transition, loss of the mitochondrial membrane potential (MMP), and mitochondrial swelling with the release of cytochrome c. These phenomena further cause apoptosome activation and caspase-mediated apoptosis (Ham and Raju, 2016). At reperfusion, there occurs a series of mitochondrial derangements, including the rapid reestablishment of oxidative phosphorylation, inhibition of respiratory chain activity, mitochondrial ROS accumulation, Ca2+ overload, mitochondrial membrane permeability transition pore (mPTP) opening, mitochondrial-dependent apoptosis, and even cell death (Ham and Raju, 2016; Wu et al., 2020a).

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Modern therapies, such as ACEIs and beta-blockers, have indirect effects on cardiac metabolism in addition to their classical effects, but they do not directly influence cardiac energy metabolism (Neubauer, 2007). Growing evidence suggests that the modulation of cardiac metabolism may be a promising therapeutic approach in patients with IHD (Noordali et al., 2018; Doehner et al., 2014; Heggermont et al., 2016). Known metabolic modulators such as Trimetazidine, L-carnitine, and Coenzyme Q10 are currently used in clinical trials. The metabolic mechanisms of these modulators mainly involve the inhibition of fatty acid oxidation, stimulation of glucose oxidation, and protection of mitochondrial function (Suner and Cetin, 2016; Di Napoli et al., 2007; Xue et al., 2007; Fotino et al., 2013). In TCM, Chinese herbal medicines are widely used in the treatment of cardiovascular diseases in clinics. CHMs have their advantages that are due to the pharmacological properties of multicomponent, multi-target, and multi-pathway. An increasing number of studies have shown that CHMs with replenishing Qi or Yang and activating blood or resolving blood stasis can regulate cardiac energy metabolism in IHD (Wong and Ko, 2013; Chen et al., 2015; Zhang et al., 2013; Li et al., 2018a).

In this article, we mainly summarize the metabolic effects and underlying mechanisms of Chinese herbal medicines, the major bioactive component of CHMs, and Chinese herbal formulas in IHD, respectively (Tables 1 and 2). In particular, the model of acute myocardial infarction is usually induced by left anterior descending (LAD) coronary artery ligation, which is the most widely used surgical animal model. The isoproterenol (Iso)-induced myocardial infarction model is a well-developed non-surgical MI model (Kumar et al., 2016). Therefore, the major inclusion criteria included the Iso-included MI model, the LAD coronary artery ligation-induced MI model, and the myocardial ischemia and reperfusion (I/R) injury model. The major exclusion criteria included exercise training, metabolomics analysis, angiotensin II-induced HF model, abdominal aorta ligation-induced HF model, cobalt chloride-induced myocardial ischemia, and doxorubicin-induced myocardial injury.

Metabolic Effects and Mechanisms of Herbs and Major Bioactive Components 

Invigorating and Replenishing Qi 

Astragalus mongholicus Bunge (Astragali Radix)

Astragalus mongholicus Bunge (Astragalus membranaceus, AM), also known as Huang-qi in China, is considered one of the major replenishing Qi medicines. Classified as a top-grade herb in "Shen Nong Ben Cao Jing", Astragalus mongholicus Bunge is widely used for the treatment of cardiovascular diseases (Ma et al., 2013). Recent studies have focused on its cardioprotective effects, especially those related to improving energy metabolism. Astragali Radix extract (ARE) exerts a cardioprotective effect against LAD ligation-induced myocardial infarction by rectifying the levels of FFA, pyruvic acid (PA), and lactic acid (LA) in serum and myocardial tissue, thereby producing more energy (Jin et al., 2014). Astragalosides are roughly extracted from Astragali Radix. Astragalosides (5 mg/kg/day, i.p.) showed protective effects by rebalancing intracellular Ca2+ homeostasis and regulating energy metabolism in Iso-induced myocardial ischemic injury. However, the mechanism of Astragalosides has yet to be reported (Chen et al., 2006). Astragaloside IV (AS-IV), a major bioactive component of the astragalosides, has been reported to improve cardiac dysfunction and modulate energy metabolism in the MI rat model. The metabolic mechanism may be mediated via the promotion of Complex V and ATP synthase delta-subunit (ATP5D) expression (Cui et al., 2018). Another trial identified the metabolic roles of ASIV in myocardial ischemia and ischemia/reperfusion injury. AS-IV also enhanced the expression of ATP5D and Complex V (Tu et al., 2013). These results indicate that AS-IV may regulate energy metabolism through mitochondrial respiration. Besides, AS-IV can modulate energy biosynthesis. Zhang et al. (2015) found that AS-IV improved cardiac hemodynamics, mediated energy

biosynthesis, and upregulated ATP5D and PGC-1a expression in Iso-induced cardiac injury. In neonatal rat ventricular myocytes (NRVMs), the cardioprotective mechanism of AS-IV may be mediated through regulating nuclear factor NF-kB/PGC-1a signaling (Zhang et al., 2015). Glycogen synthase kinase-3b (GSK-3b), a serine/threonine protein kinase, interacts with mitochondrial proteins such as PI3K-Akt, PGC-1a, and subunits of mPTP, which plays an essential role in relating to mitochondrial biogenesis, mitochondrial permeability, and glycogen metabolism (Yang et al., 2017a). Formononetin is the main isoflavonoid compound of Radix Astragali. Formononetin enhanced GSK-3b and Akt phosphorylation in H9c2 cells during oxygen-glucose deprivation (OGD) and reoxygenation, thereby reducing GSK-3b activity towards mPTP opening (Cheng et al., 2016). Kaempferol, a natural flavonoid, exists in Astragalus mongholicus Bunge and Panax ginseng C.A.Mey. Kaempferol showed cardioprotective effects via mitochondrial pathway against ischemia/reperfusion injury in NRVMs. The cardioprotective mechanisms may be mediated by SIRT1 (Guo et al., 2015). Astragalus polysaccharides (AP) could improve cardiac energy biosynthesis and prevent Iso-induced cardiac ischemic injury by regulating tumor necrosis factor TNF-a/PGC-1a signaling-mediated energy biosynthesis, both in vivo and in vitro. Among them, ATP5D, PGC-1a, and pyruvate dehydrogenase kinase isoform 4 (PDK4) all increased, which means AP may be related to energy metabolism (Luan et al., 2015).

Panax ginseng C.A.Mey. (RG) 

Panax ginseng C.A.Mey.(Radix ginseng), also known as Ren Shen, is well known for its "Qi-Replenishing" effect in TCM and is listed as a top-grade herb in "Shen Nong Ben Cao Jing". In the last decade, the representative active ingredients of Radix ginseng (including Ginsenoside Rb1, Ginsenoside Rd, Ginsenoside Rg1, Ginsenoside Rg5, Panax ginseng Polysaccharide, and total ginsenosides) have been demonstrated to exert significant effects on energy metabolism. Ginsenoside Rb1(Rb1), a major effective ingredient of Panax ginseng, has been shown to modulate energy metabolism in myocardial ischemia and reperfusion injury, hypertrophy, and even HF (Zheng et al., 2017). In rat models of myocardial infarction, Rb1 could increase the expression of the mitochondrial ATP5D and complex V (Cui et al., 2018). In ischemia/reperfusion injury, Rb1 reduced the infarction sizes, inhibited mPTP opening, restored the MMP, and upregulated the p-AKT and p-GSK-3b expression. These results indicate that the protective effects of Rb1 against I/ R-induced myocardial injury may be associated with the protection of mitochondrial function (Li et al., 2016b). Similarly, Rb1 could protect cardiac myocytes and modulate energy metabolism against I/R-induced myocardial injury via the RhoA signaling pathway (Cui et al., 2017). Ginsenoside Rd (Rd) is another biologically active extract from Panax ginseng C.A.Mey. Wang et al. (2013)found that Rd exerted cardioprotective effects by stabilizing the MMP and attenuating the release of mitochondrial cytochrome c in myocardial ischemia/reperfusion injury. As a major compound of Radix ginseng, Ginsenoside Rg1 (Rg1) modulated energy metabolism in ischemia/reperfusion injury by enhancing ATP content and the activity of mitochondria respiratory chain complexes, which might partially be related to its binding to RhoA and consequent the inhibition of RhoA/ROCK pathway (Li et al., 2018b). In vitro, Rg1 treatment (12.5 mM) exerted a cardioprotective effect by regulating mitochondrial dynamics and was achieved by moderating glutamate dehydrogenase (GDH) and MFN2 dysregulation. However, Rg1 had no significant effects on MFN1, OPA1, and Drp1 (Dong et al., 2016). Mitochondrial hexokinase-II (HK-II), as a key molecule in glycolysis, can keep mitochondrial integrity and prevent mitochondrial death (Roberts and Miyamoto, 2015). Ginsenoside Rg5 (Rg5) ameliorated the iso-induced ischemic myocardium injury by inhibiting fatty acid oxidation and regulating mitochondrial dynamics imbalance. Rg5 may improve mitochondrial dysfunction by regulating mitochondrial HKII binding and reducing Drp1 recruitment to mitochondria via Akt activation (Yang et al., 2017c). Panax ginseng Polysaccharide (PGP) had cardioprotective effects and protected mitochondrial function in myocardial I/R injury. In vitro, PGP reduced the release of mitochondrial cytochrome c, maintained the MMP, and restored mitochondrial respiration (Zuo et al., 2018). Total ginsenosides (TGS) of RG have been reported to enhance energy metabolism by increasing glucose metabolism and activating TCA cycle-related protein expression in ischemic rat myocardium (Wang et al., 2012).

Rhodiola rosea L. (RR) Rhodiola rosea L., a well-known plant in Tibet, has been demonstrated to treat a diverse range of cardiovascular conditions, including IHD, arrhythmia, and angina pectoris (Yu et al., 2014; Liu et al., 2016). Salidroside (SAL) is the main component extracted and purified from Rhodiola. Chang et al. (2016) reported that SAL had cardioprotective effects by regulating energy metabolism in coronary artery occlusion-induced myocardial injury. SAL enhanced the ATP and glycogen content through AMPK/PGC-1aaxis and AMPK/NFkB signaling pathways (Chang X. Y. et al., 2016).

Ganoderma Lucidum (GL) 

Ganoderma lucidum (Reishi mushroom), popularly known as Lingzhi in Asian countries, has antioxidative and cardioprotective effects. Ganoderma lucidum extract ameliorated myocardial ischemic injury by improving mitochondrial dysfunction in induced myocardial infarction rats. The mechanism may be related to the activities of the enzymes of the TCA cycle and mitochondrial respiratory chain complexes such as complexes I, II, III, and IV (Sudheesh et al., 2013). Ganoderma atrium polysaccharide (PSG-1) is regarded as a major bioactive ingredient in Ganoderma Lucidum. Li et al. (2010) reported that PSG-1 protected cardiomyocytes by mitochondrial pathways in hypoxia/reoxygenation-induced NRVM injury. PSG-1 reduced the release of cytochrome c from the mitochondria into cytosol and enhanced MMP levels (Li et al., 2010).

Gynostemma pentaphyllum (Thunb.) Makino (GPM) 

As one of the replenishing Qi medicines, Gynostemma pentaphyllum (Thunb.) Makino exerts anti-hypertensive, anti-hyperlipidemia, anti-inflammation, and anti-aging effects (Zhang et al., 2018a). Gypenosides (GP) are the major saponins of Gynostemma pentaphyllum, which possess cardioprotective effects in myocardial infarction rats. Yu et al. (2016) found that GP significantly reduced myocardial infarct size and protected mitochondrial function in myocardial ischemia-reperfusion injury. GP enhanced the levels of ATP, regulated enzymatic activities of the mitochondrial respiration chain, and maintained the mitochondrial membrane integrity (Yu et al., 2016).

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