Modulatory Effects Of Chinese Herbal Medicines On Energy Metabolism in Ischemic Heart Diseases Part Ⅱ

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Replenishing and Activating Blood

Panax notoginseng (Burkill) F.H.Chen (PNG)

Panax notoginseng (Burkill) F.H.Chen, known as San qi, San chi, and/or Tian qi inChina, is a blood-replenishing and stasis-resolving TCM herb widely used in the treatment of cardiovascular diseases. Panax Notoginseng can reduce MI size and CK levels in rat models of myocardial ischemia (Han et al., 2013). There are three main saponins of Panax Notoginseng, including Rg1, Rb1, and Notoginsenoside R1 (R1). R1 is the major effective component of Panax notoginseng and exerts significant cardioprotective effects by preventing the dysregulation of energy metabolism. The energy metabolism-associated modulatory mechanism of R1 may be mediated through inhibiting the activity of ROCK, and elevating ATP5D expression and ATP content in ischemia/reperfusion-induced myocardial injury (He et al., 2014).

Salvia miltiorrhiza Bunge (SM)

Salvia miltiorrhiza Bunge (also called Danshen), another bloodreplenishing and stasis-resolving TCM herb, has shown therapeutic promise for multiple cardiovascular diseases. Salvianolic acid A (Danshensu) is one of the major water-soluble compounds derived from Salvia miltiorrhiza and has been reported to alleviate cardiac I/R injury by inhibiting MPTP opening and expression of the ATP synthase c-subunit (Gao et al., 2017). 3, 4-Dihydroxylphenyl lactic acid (DLA) is another name for Salvianic acid A, which has been demonstrated to reduce infarction size and enhance mitochondrial aerobic respiration in myocardial I/R injury. NADH dehydrogenase 1 alpha subcomplex 10 (NDUFA10) belongs to one of the subunits of mitochondrial Complex I. DLA may regulate the mitochondrial respiration via enhancing the NDUFA10 and SIRT1 expression (Yang et al., 2015). Sirtuin3 (SIRT3), another NAD+ -dependent deacetylase in addition to SIRT1, modulates the succinate dehydrogenase complex, subunit A, flavoprotein variant (SDHA). Total Salvianolic Acid Injection (TSI) is a preparation of an active compound extracted from Salvia miltiorrhiza Bunge. TSI had significant cardioprotective effects by regulating mitochondrial respiratory chain in ischemia/reperfusion-induced myocardial injury. TSI reduced infarction size and enhanced NDUFA10 and SDHA protein expression via the activation of SIRT1 and SIRT3 (Huang et al., 2019). Tanshinone IIA (TIIA), another monomer isolated from the Salvia miltiorrhiza, has been reported to protect cardiac function against MI and I/R injury. Jin and Li (2013) found that TIIA protected mitochondrial function in hypoxia-induced H9c2 cells injury, which might involve the regulation of mitochondrial ROS generation, ATP content, and intracellular nitric oxide (NO) levels (Jin and Li, 2013). However, the mechanism of TIIA has yet to be revealed.

Carthamus tinctorius L

Carthamus tinctorius L (CTL) is widely used in Asian countries, which exerts significant capacity of anticoagulation, increasing coronary blood flow, and treating ischemic cardiovascular diseases (Zhou et al., 2014). Hydroxysafflflor Yellow A (HSYA) is a major representative ingredient of Carthamus tinctorius L. HSYA signifificantly reduced the blood CK-MB and LDH levels, mitochondrial ROS accumulation, and the loss of MMP in isoinduced myocardial ischemic injury. In vitro, HSYA markedly increased the PGC-1a and Nrf2 protein expression in H9c2 cells subjected to OGD injury (Chen et al., 2016). HKII, located on the outer mitochondrial membrane, regulate cardiac mitochondrial function and cellular glucose metabolism (Roberts and Miyamoto, 2015). Min and Wei (2017) dived more deeply into the cardioprotective mechanism of HSYA in ischemia-reperfusion myocardial injury. They found that HSYA exerted cardioprotective effects by restoring mitochondrial energy metabolism. This mechanism of HSYA may be mediated via Akt/HKII independent of the ERK/GSK-b signal pathway. Taken together, these results suggest that HSYA effectively improves myocardial injury in pre-clinical models of myocardial ischemia.

Boswellia serrata Roxb.

Boswellia serrata Roxb. (BSR) is considered as one of the major promoting blood circulations for relieving pain TCM herb. The combination of Carthamus tinctorius L and Boswellia serrata Roxb. is widely used for treating ischemic heart disease (Chen et al., 2016). Acetyl-11-keto-b-boswellic acid (AKBA) is recognized as the main component of Boswellia serrata Roxb., which has similar cardioprotective actions as Hydroxysafflflor Yellow A in H9c2 cells subjected to OGD injury. AKBA effectively improved mitochondrial membrane potential levels and increased the PGC-1a and Nrf2 protein expression, suggesting that the beneficial role of AKBA in OGD-induced myocardial ischemic injury can be attributed to the improvement of mitochondrial biogenesis (Chen et al., 2016).

Invigorating and Replenishing Yang

Cistanche deserticola Ma

Cistanche deserticola Ma, also known as Herba Cistanche (HC), is a “Yang-invigorating” Chinese tonic herb. Herba Cistanche extracts protected against myocardial ischemia/reperfusion injury by enhancing mitochondrial ATP generation. Glutathione (GSH) is the first defense line against oxidative damage. Herba Cistanche extract may enhance mitochondrial respiration through increasing mitochondrial GSH levels, decreasing mitochondrial oxidized glutathione (GSSG), improving MMP, and reducing mitochondrial Ca2+ levels (Siu and Ko, 2010). Another study reported the cardioprotective effect of Herba Cistanches fraction (HCF1) in vitro and in vivo. In vitro, HCF1 at 30 ng/mL signifificantly enhanced mitochondrial ATP generation capacity (ATP-GC), mitochondrial ROS production, and mitochondrial respiration. In vivo, HCF1 signifificantly enhanced mitochondrial GSH status and enhanced ATP-GC content in I/R adult female rats. Surprisingly, they found that low-dose HCF1 signifificantly reduced tissue ATP levels in non-I/R rats, whereas the depletion of tissue ATP level by HCF-1 was reduced in I/R rats. This phenomenon in non-I/R rats may be related to HCF-induced sustained mitochondrial uncoupling, while in I/R rats it may be related to the increase in ATP-GC by HCF-1 (Wong and Ko, 2013). b-sitosterol (BS), as a hydrophobic compound of HCF1, reduced LDH levels and increased the cellular glutathione redox cycling in myocardial I/R female rats. But BS had no significant effects on mitochondrial ATP-GC in male or female rat myocardium (Wong et al., 2014). Therefore, the effects of mitochondrial ATP-GC in Cistanche deserticola Ma extract may depend on other compounds, which need to be further studied.

Cynomorium coccineum subsp. songaricum (Rupr.) J.Léonard

Cynomorium coccineum subsp. songaricum (Rupr.) J. Léonard (also called Cynomorii herba) (CCS), another “Yang-invigorating” Chinese tonic herb, is found to enhance mitochondrial ATP-GC in H9c2 cells. Chen and Ko (2013) isolated bioactivate fraction (HCY2) and ursolic acid (UA) from cynomorii herba. They demonstrated that HCY2 and UA could protect myocardial ischemia/reoxygenation in male and female rats. HCY2 and UA may protect mitochondrial function by reducing LDH levels, enhancing cardiac tissue ATP and mitochondrial ATP-GC levels, and upregulating the mitochondrial GSH/GSSG ratio and glutathione reductase (GR) activity

Other Extractive Compounds of Chinese Herba

Berberine

Berberine, an isoquinoline alkaloid isolated from Coptis Chinensis Franch., is widely used in the treatment of diarrhea in Asian countries. Wang et al. (2015b) reported that berberine (200 mg/kg/day) exerted cardioprotective effects by attenuating myocardial apoptosis and improving mitochondrial dysfunction in myocardial ischemia/reperfusion. However, the metabolic mechanism of berberine remains unclear. Berberine treatment (100 mg/kg/day, i.g.) improved cardiac function and reduced infarction size. Berberine may have cardioprotective effects through regulating AMPK phosphorylation in ischemia-reperfusion myocardial injury. Interestingly, they found that berberine downregulated p-AMPK expression, and decreased the ADP/ATP and AMP/ATP ratio in peri-infarct areas. In contrast, berberine upregulated p-AMPK expression and increased the ADP/ATP and AMP/ATP ratio in non-ischemia areas. However, this phenomenon has yet to be revealed (Chang et al., 2012).

Crude Terpene Glycosides

Crude terpene glycosides (CS-TG), as the major active components in Paeonia lactic flora Pall., include paeoniflorin, albiflorin, and enzoylpaeoniflorin. Crude terpene glycosides have been shown to attenuate cardiac hypertrophy, inhibit cardiomyocyte apoptosis and promote blood flow (Ke et al., 2017). Ke et al. (2017) conducted the myocardial ischemia model in rats fed with 300 mg/kg/day CS-TG. CS-TG signifificantly decreased CK and LDH levels in serum and improved energy metabolism. Rats treated with CS-TG improved energy metabolism in ISO-induced myocardial ischemic injury, which might be related to increasing the ATP and glycogen content, protecting mitochondrial ultrastructure, and decreasing p-AMPK expression (Ke et al., 2017). In contrast, many studies indicated that the activation of AMPK phosphorylation promotes energy metabolism by regulating glucose and lipid metabolism (Luiken et al., 2003; Russell et al., 2004; Qi and Young, 2015). AMPK activation also promotes mitochondrial fission via MFF phosphorylation (Garcia and Shaw, 2017). The inconsistency between the upregulation and downregulation on AMPK phosphorylation during ischemia may depend upon the cell type, myocardial ischemic model, pathophysiological setting, and ischemic duration. Besides, inhibition of AMPK is likely to involve other mechanisms such as myocardial acidosis and apoptosis.

Ginkgo biloba L. Extract

Ginkgo biloba L. (GBE) extract is one of the most commonly used herbs and exhibits multiple pharmacological activities. GBE has been widely used for the treatment of cardiovascular diseases.

A study by Wang et al. (2016b) reported that GBE (200 mg/kg/ day) pretreatment could signifificantly restore fatty acid, glyceride, and amino acid levels, thereby exerting cardioprotective effects in ISO-induced myocardial ischemia in rats. Another study found that GBE treatment uncoupled mitochondrial oxidative phosphorylation and reduced the mitochondrial free radicals in ischemic rat hearts for 10 and 18 days (Bernatoniene et al., 2011).

Luteolin

Luteolin is a polyphenolic compound derived from vegetables, fruits, and medicinal herbs. In vivo, Hu et al. (2016) reported that Luteolin could improve cardiac dysfunction in wild-type mice after myocardial infarction. Meanwhile, luteolin treatment was shown to enhance MMP levels, ATP content, citrate synthase (CS) activity, and the activities of complexes I-V induced by hypoxia in neonatal mice ventricular cardiomyocytes. The cardioprotective effects of luteolin associated with improvement in mitochondrial biogenesis may be exerted through inhibition of mammalian sterile 20-like kinase 1 (Mst1) expression.

Quercetin

Quercetin, a flavone used as a food supplement, exerts powerful antioxidant effects. Punithavathi and Prince (2010) demonstrated that quercetin reduced myocardial infarct size and prevented mitochondrial dysfunction in isoproterenol-treated myocardial infarcted rats. Another study also found quercetin (10 mg/kg) pre-treatment elicited cardioprotective effects, including ameliorating lipids accumulation and altering the levels of lipoproteins and enzymes involved in lipid metabolism in isoproterenol-treated myocardial infarcted rats (Prince and Sathya, 2010). However, the protective mechanism remains unclear.

Resveratrol

Resveratrol is a natural polyphenol from many plant-based foods, including blueberries, grapes, and cranberries. Multiple studies have reported that resveratrol exerts cardioprotective effects (Kanamori et al., 2013; Sung et al., 2015; Fourny et al., 2019). Kanamori et al. (2013) investigated the effects of resveratrol in myocardial infarction mice and found that resveratrol could improve myocardial energy status by enhancing the ATP content and increasing the p-AMPK activation. Furthermore, Fourny et al. (2019) also focused on the cardioprotective effects of resveratrol against I/R injury, which is related to improving mitochondrial dysfunction. They found that the underlying mechanism may be associated with increased expression of p-AKT, eNOS, and SIRT1, resulting in improved energy metabolism.

Tetrandrine

Tetrandrine (TTD), a bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra S. Moore, has been shown cardioprotective effects on myocardial fibrosis and myocardial infarction (Teng et al., 2015). In vivo, tetrandrine (50 mg/kg) pretreatment signifificantly improved cardiac function, reduced infarct size, and decreased blood LDH levels in myocardial ischemia and reperfusion injury. In neonatal rat cardiomyocytes, tetrandrine treatment (10 mM) signifificantly reduced mitochondrial ROS accumulation, stabilized the MMP, attenuated mitochondrial cytochrome c release, and enhanced p-AKT and p-GSK-3b protein expression. This phenomenon may be related to mitochondrial function (Yang et al., 2017b).

Metabolic Effects of Chinese Herbal Formulas and the Associated Mechanisms

In addition to herbs and the major bioactive components described above, we also summarize the metabolic effects and associated mechanisms of Chinese herbal formulas in IHD. Chinese herbal formulas (including decoctions, Chinese patent drugs, and injections), which refer to the combination of specific herbs based on TCM theory, are widely used in Chinese clinical practice. However, the research of formulas has faced numerous obstacles and challenges because of the complexity associated with pharmacological properties of multi-herb, multi-component, and multi-target. In recent years, researchers begin to address the complexity of biology in formulas from a systems perspective using modern science and advanced technologies such as quality control, metabonomics, and molecular biology. The new technologies are important for ensuring standardization and industrialization of CHMs and identifying the optimal treatment for cardiovascular diseases.

Decoctions

Buyang Huanwu Decoction

Buyang Huanwu Decoction (BYHWD), a classic TCM formula of qi-replenishing and stasis-eliminating method, is containing Astragalus mongholicus Bunge, Angelica Sinensis (Oliv.) Diels, Radix Paeoniae Rubra, Ligusticum striatum DC, Pheretima, Semen Persicae, and Carthamus tinctorius L. BYHWD may relieve MI injury through regulating energy metabolism in rats with coronary heart disease (Wang et al., 2011). However, the metabolic mechanism of BYHWD has yet to be revealed.

Shengmai San

Shengmai San (SMS), a well-known TCM prescription comprising Panax ginsengC.A.Mey, Ophiopogon japonicas(Thunb.) Ker Gawl, and Schisandra chinensis (Turcz.) Baill is widely used to treat coronary artery disease, angina pectoris, and HF in clinical practice. SMS water extract signifificantly improved cardiac function, increased ATPase activity during 3 weeks in the MI-induced heart failure mice model. In vitro, SMS (400 µg/mL) could improve mitochondrial function by enhancing MMP and ATP levels. Besides, SMS inhibited phosphorylation of Drp1 at Ser 616 and increased phosphorylation of Drp1 at Ser 637 in OGD-induced cardiomyocytes injury (Yang et al., 2017d). Drp1 has two major phosphorylation sites. Phosphorylation of Drp1 at Ser616 leads to mitochondrial fission, while Drp1 phosphorylation at Ser637 inhibits mitochondrial fission and induces mitochondrial fusion and elongation (Willems et al., 2015). These results indicate that the mechanism of SMS may be associated with inhibiting mitochondrial fission through the Drp1 signaling pathways.

Yiqihuoxue Decoction

Yiqihuoxue Decoction (YQHX) is designed based on the Danggui Buxue decoction (DBD) TCM formula, which is a recognized treatment for IHD with Qi deficiency and blood stasis syndrome. Li et al. (2018a) reported that a 28-day administration of YQHX, a formulation containing Astragalus membranaceus, Angelica Sinensis (Oliv.) Diels, Panax ginseng, Ligusticum striatum DC., and Panax notoginseng, could signifificantly improve cardiac function and mitochondrial function in myocardial ischemic rats with LAD surgery. YQHX treatment signifificantly increased PGC-1a expression, improved the mitochondrial ultrastructure, and increased mitochondrial ATP content. In vitro, YQHX largely reduced LDH and ROS levels, restored the mitochondrial morphology, and increased MMP. Meanwhile, YQHX upregulated PGC-1a and NRF-1 protein expression through the activation of p-AMPK phosphorylation induced by ischemia/ hypoxia-induced H9c2 cells injury. Among them, AMPK, PGC- 1a, NRF-1, and Tfam are all increased which means that the cardioprotective effects of YQHX may be related to improving mitochondrial dysfunction.

Gualou Xiebai Decoction

Gualou Xiebai Decoction (GLXB), a classic TCM prescription, is widely used for the treatment of cardiac heart diseases. GLXB is composed of Trichosanthis Pericarpium, Allium macrostemon Bunge, and wine has been proposed in AD 200–205 by famous doctor Zhang Zhong-Jing. Rats treated with GLXB exhibited a significant reduction in myocardial infarct size, as well as improved cardiac function and myocardial structure following myocardial I/R injury, which was likely achieved through the modulation of energy metabolism via the inhibition of the RhoA/ ROCK signaling pathway (Yan et al., 2018).

Chinese Patent Drugs

QishenYiqi Capsule

Qishen Yiqi capsule (QSYQ), a clinically used formula consisting of extracts from Astragalus membranaceus, Salvia miltiorrhiza Bunge, Panax notoginseng, and Dalbergia odorifera, has been approved for clinical use in China and is widely used to treat cardiovascular diseases such as IHD, angina pectoris, and ischemic HF (Jianxin et al., 2016; Zhang et al., 2018b). Recent pharmacological studies showed that QSYQ could modulate energy metabolism and improve cardiac function in ischemic rats with LAD coronary artery ligation (Cui et al., 2018; Zhang et al., 2018d). Zhang et al. (2018d) identified 24 chemical ingredients in QSYQ via UPLC-Q-TOP/MS in the negative and positive modes. QSYQ treatment could alleviate mitochondrial dysfunction and protect nuclei number and mitochondrial mass against hypoxia/ ischemia-induced injury, however, the metabolic mechanism has yet to be revealed. Similarly, QSYQ has been shown to regulate energy metabolism in a rat model of cardiac I/R injury (Lin et al., 2013; Chen et al., 2015).

Qiliqiangxin Capsule

Qiliqiangxin capsule (QLQX) is an 11-herb Chinese medication widely used for treating myocardial infarction and even congestive heart failure in clinical practice. In ovariectomized mice, QLQX (0.5 g/kg) treatment signifificantly attenuated cardiac remodeling and facilitated energy metabolism after myocardial infarction by upregulating the expression of lipid metabolism-related genes and activation of PPARg (Shen et al., 2017). In rat primary cardiac microvascular endothelial cells (CMECs) subjected to hypoxia, QLQX was found to improve glucose utilization and protect CMECs against hypoxia-induced injury by promoting hypoxia-inducible factor 1-alpha (HIF-1a)-dependent glycolysis (Wang et al., 2018a). Zhao et al. (2019) conducted the myocardial infarction surgery in male SD rats fed with (0.25, 0.5, and 1.0 g/kg/day) QLQX. 4 weeks after myocardial infarction, QLQX treatment protected cardiac function, ameliorated mitochondria-dependent apoptosis, and enhanced p-AKT and pGSK3b expression. In addition, QLQX also regulated mitochondrial fission, reduced mPTP opening, and enhanced MMP levels in oxidative stress-induced cardiomyocytes injury. Taken together, these findings indicate that QLQX may regulate energy metabolism by increasing lipid metabolism, improving glucose utilization, and regulating mitochondrial fission.

Compound Danshen Dripping Pill

Compound Danshen dripping pill (CDDP) consists of Radix Salvia miltiorrhiza, Radix Notoginseng, and Borneolum, which is widely used for treating ischemic heart diseases. Guo et al. (2016) generated a rat model of acute myocardial ischemia induced by isoproterenol and found that CDDP pretreatment could increase ATP production and modulate metabolomic patterns in ischemic rat myocardium through promoting a metabolic shift toward fatty acids metabolism.

DanQi Pill

DanQi pill (DQP) is composed of two herbs, namely, Salvia Miltiorrhiza and Panax Notoginseng. The formulation is listed in Chinese Pharmacopoeia of 2010 and is widely used for the clinical treatment of IHD. Recent pharmacological studies showed that DQP treatment could signifificantly improve cardiac function and modulate lipid metabolism in rat models of MI (Wang et al., 2015a; Chang H. et al., 2016; Wang et al., 2016a; Jiao et al., 2018), as well as promote a significant increase in the expression of CPT-1A, CD36, and PPARa. Among them, CPT-1A, CD36, and PPARa expressions are all increased which means that the metabolic mechanism of DQP may be associated with lipid metabolism. Zhang et al. (2018c) conducted HF after MI rat models and oxygen-glucose deprivation-reperfusion (OGD/R)-induced H9c2 cell, injury models. They found that DQP had similar actions as a selective PPARg activator (Rosiglitazone), which rescued cardiac function, and regulated key factors in lipid and glucose metabolism in the MI-induced HF rat model through the PPARg pathway. To further certain the metabolic mechanism of DQP on PPARg, H9c2 cells were treated with/without PPARg inhibitor (T0070907) and DQP. They found that the increase of ATP content and PPARg expression of DQP could be inhibited by T0070907 in OGD/Rinduced H9c2 cell injury. Besides, DQP has also been suggested to regulate energy metabolism in rat ischemic myocardium through the AMPK/SIRT1-PGC-1a signaling pathway (Meng et al., 2019).

Yangxinshi Tablet

Yangxinshi tablet (YXS) is composed of 13 herbs, which have been widely used to prevent and treat chest tightness, angina pectoris, and coronary heart disease. It is widely used in replenishing Qi, activating blood circulation, and resolving blood stasis in clinics. Zhang et al. (2018b) found 25 metabolites from metabolic profiles in ischemia-reperfusion injury. The metabolites were mainly involved in energy metabolism, fatty acid metabolism, and amino acid metabolism. However, the mechanism of YXS needs to be further explored. Another study dived more deeply into the cardioprotective mechanism of YXS. YXS treatment signifificantly decreased infarct size, protected cardiac function, and improved energy metabolism in rats with chronic ischemic heart failure. YXS improved energy metabolism through increasing p-AMPK, PGC-1a, GLUT4, and HIF-1a expression (Wu et al., 2020b).

Injections

Shengmai Injection

Shengmai injection (SMI) was approved by the China Food and Drug Administration (CFDA) in 1995, which has been widely used to prevent and treat coronary heart disease and chronic HF. SMI is composed of two herbs, including Panax ginseng C.A.Mey. and Ophiopogon japonicus (Thunb.) Ker Gawl. Wang et al. (2018b) applied an iTRAQ-based proteomic approach to identify differentially expressed proteins of SMI, and found that their function was associated with mitochondrial oxidative phosphorylation. SMI signifificantly increased ATP5D, NDUFB10, and TNNC1 protein expression in rats with myocardial ischemic injury. In vitro, SMI increased ATP and MMP content and had positive effects on mitochondrial respiration induced by hypoxia. Another trial identified the metabolic effects of SMI against ischemia-reperfusion injury. SMI reduced the mitochondrial mass, enhanced MMP, and inhibited mPTP opening. SMI treatment increased MFN1, MFN2, and OPA mRNA expression, and reduced Drop and Fis mRNA expression. These results mean that the cardioprotective effect of SMI may be associated with mitochondrial dynamics (Yu et al., 2019).

Xuesaitong Injection

Xuesaitong injection (XST) is mainly composed of Panax Notoginseng saponins, which has been widely used to prevent and treat cardio-cerebral vascular diseases. XST treatment enhanced the PDH activity, a key enzyme converted pyruvate to acetyl CoA in mitochondria and related to TCA cycle, as well as increased Na+ -K+ -ATPase and Ca2+-Mg2+-ATPase, and elevated intracellular ATP and acetyl-CoA levels in hypoxia/ reoxygenation condition. XST signifificantly enhanced pyruvate dehydrogenase E1 alpha (PDHA1) and ATP synthase 5A (ATP5A) protein expression in H9c2 cells with hypoxia/ reoxygenation injury. These proteins are mainly associated with cardiac energy metabolism (Zhao et al., 2017).

YiQiFuMai Powder Injection

YiQiFuMai powder injection (YQFM) is designed based on the well-known TCMs prescription Shengmaisan, which is widely applied for the treatment of angina pectoris, coronary heart disease, and chronic heart failure. YQFM is composed of three herbs, including Panax ginseng C.A.Mey., Ophiopogon japonicas (Thunb.) Ker Gawl, and Schisandra chinensis (Turcz.) Baill. YQFM signifificantly attenuated coronary artery ligationinduced heart failure via improving cardiac function and attenuating mitochondrial dysfunction in mice. In addition, YQFM signifificantly inhibited the Drp1 phosphorylation at Ser616 and increased Mfn2 expression in HF mice and OGDinduced NRVMs injury (Zhang et al., 2019). It indicates that YQFM may improve energy metabolism by regulating mitochondrial dynamics. In a different study described in ischemia/reperfusion-Induced myocardial injury, YQFM might regulate energy metabolism through the activation of AMPK phosphorylation (Li et al., 2016a).

CONCLUSIONS AND PERSPECTIVES

Over the last decade, increasing attention has been focused on the modulation of cardiac energy metabolism as a therapy for the treatment of cardiovascular diseases (Neubauer, 2007). The modulation of cardiac energy metabolism, a complex process involving substrate utilization, mitochondrial oxidative phosphorylation, and ATP transfer and utilization, plays a key pathophysiological role in both cardiac disease progression and its treatment (Figure 1). The cardiac metabolic network has complexity and high flexibility in energy substrate utilization during hypoxic/ischemic conditions. In the early stages of cardiac remodeling, alterations in myocardial substrate selection are partly considered to be a compensated and protective mechanism that may impede cardiac irreversible damage. In contrast, in advanced stages, persistent ischemia/hypoxia and subsequent reperfusion may lead to a decrease in fatty acid oxidation and an increase in glucose oxidation, which further contributes to lipotoxicity, lactic acidosis, low ATP production, contractile dysfunction, and progression to HF. This process indicates that the relationship between cardiac energy metabolism and IHD is double-sided. Balancing the contradictory effects of energy metabolism at different time points may enhance drug efficacy in the treatment of IHD.

Chinese herbal medicines have great therapeutic potential for the treatment of IHD through the modulation of cardiac metabolism. In this review, we mainly summarize the metabolic effects and the underlying mechanisms of herbs, major bioactive components, and Chinese herbal formulas in IHD. Multiple signal pathways and multiple targets are associated with CHMs-mediated effects on energy metabolism in IHD (Figure 3). The details are as follows: (1) The mechanisms of herbs, MBC, and CHF in attenuating MI-induced energy metabolism disorder may mainly involve promoting mitochondrial biogenesis, regulating fatty acid and glucose metabolism, modulating mitochondrial respiratory, and maintaining the balance of mitochondrial dynamics. (2) Chinese herbal formulas that can modulate energy metabolism in IHD usually contain Qi-replenishing and/or Blood-activating herbs. Furthermore, Qi-replenishing and/or Blood-activating CHMs, especially Qi-replenishing herbs and their major components, often play a key role in regulating energy metabolism in IHD. It suggests that the Qi-replenishing effects of CHMs may be related to regulating energy metabolism, especially mitochondrial function. (3) Besides, Qi-replenishing herbs or a combination of Qireplenishing and Blood-activating herbs may produce better efficacy on cardiac energy metabolism than monotherapy with Blood-activating herbs. Taking QSYQ as an example, Cui et al. (2018) compared the contribution of five major components (ASIV, Rb1, Rg1, R1, and DLA) in QSYQ and QSYQ to their potential to regulate energy metabolism in ischemia-induced rat myocardial injury. They found that QSYQ and its five components could improve cardiac structure. Especially, QSYQ signifificantly improved cardiac function and modulated energy metabolism. The mechanism of QSYQ may prevent ischemia-induced rat myocardial injury by increasing the ATP content, enhancing cTnI and ATP5D expression, and improving the ATP synthase activity. However, five components of QSYQ had different effects on regulating energy metabolism. AS-IV and Rb1 treatment could increase the ATP levels, ATP5D protein expression, and ATP synthase activity, respectively. In contract, R1 only signifificantly enhanced the cTnI protein expression. Rg1, R1, and DLA of QSYQ had no effects on ATP production, ATP5D expression of ATP synthase activity. These data indicate that the five components in QSYQ exert synergistic effects, promoting ATP production, cTnI and ATP5D expression, and ATP synthase activity. Among them, AS-IV and Rb1 belong to the compounds of Qi-replenishing herbs, whereas R1 and DLA belong to the compounds of Blood-activating herbs. Therefore, the cardioprotective effect of CHMs on energy metabolism in myocardial ischemia may mainly depend on the synergistic effect of combinations of Qi-replenishing and Bloodactivating CHMs. Furthermore, studies may provide the structural basis for the effect of major bioactive compounds from CHMs. Major bioactive compounds with energy metabolism regulatory activity identified in CHMs, such as AS-IV, Rb1, Rg1, Rd, and R1, mainly belong to the group of saponin compounds that are primarily extracted from Astragalus membranaceus, Panax ginseng, and Panax notoginseng, respectively. These possess the ability to regulate mitochondrial biogenesis and mitochondrial respiration through multiple targets and pathways

Currently, the effects and mechanisms of CHMs on cardiac energy metabolism are still unclear and partially contradictory in experimental studies, which can be primarily attributed to the complex chemical and pharmacological properties of Chinese herbal medicines. The further establishment of the platform of studies on TCM complex prescriptions and their decomposed recipes is essential to clarify the compatibility interactions of different traditional Chinese medicines. Meanwhile, we should pay more attention to the preclinical toxicology study to ensure the herbs’ safety and efficacy of improving energy metabolism in IHD. Cardiac energy metabolism after myocardial ischemia is a dynamic and highly flexible process. Further study needs to compare the change of energy metabolism in different time periods after myocardial ischemia. Additionally, there is a series of complex pathological processes induced by various pathogenetic factors in IHD, which is accompanied by other symptoms and combined with other cardiovascular diseases. However, common animal models are often designed only for a single-factor intervention. Thus, we need to design more combination models such as a rat model of MI combined with diabetes, which is closer to the clinical practice. In clinical trials, although TCMs have a long history of clinical applications in the treatment of IHD, high-quality evidence for their effectiveness is still generally lacking. The clinical research of modern Traditional Chinese Medicine remains many practical problems, including the insufficient understanding of clinical trial registration, the underdevelopment of clinical methodology, imperfect quality control systems, and non-standard clinical research reports (Zhang et al., 2013). Therefore, further clinical studies, including more rigorously designed randomized, double-blind, and large-scale controlled trials are required and should involve investigating different dosages, administration times, dosing regimens, and delivery routes. Meanwhile, there is a need to urge researchers to perform the international registration of clinical trials, which further improves the experiment design and avoids selection and reporting bias. The further strengthening assessment of adverse reactions of TCMs is essential to enhance the accuracy of clinical evaluation and reduce the occurrence of adverse drug reactions. Additionally, we must pay more attention to the negative outcomes associated with medication to ensure the integrity and facticity of TCMs results in clinical research. Currently, most clinical studies of TCM prescriptions in IHD often use the placebo as a control group and lack comparisons to clinical drugs. Thus, the design of clinical research needs to compare the western medicine control group to evaluate the efficacy of TCM. The characteristics of TCM such as the theory of treatment based on syndrome differentiation also increase the complexity and difficulty of clinical research. It is necessary to further establish a new qualitative and quantitative research of the mixed-methods approach to adapt to the characteristics of traditional Chinese Medicine.

AUTHOR CONTRIBUTIONS

FL conceived the topic and wrote the manuscript. JL and SL helped to revise the manuscript and draw the figure and consult the references. SG and PL revised and modified the manuscript.

FUNDING

This work is supported by the National Natural Science Foundation of China (No. 81473552), and the Postdoctoral Science Foundation of China (No. 2019TQ0043).