The inhibitory role of Chinese materia medica in cardiomyocyte apoptosis and underlying molecular mechanism

Biomedicine & Pharmacotherapy 118 (2019) 109372

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Review

The inhibitory role of Chinese materia medica in cardiomyocyte apoptosis and underlying molecular mechanism

T

⁎

YuZhen Li , XiuHua Liu Department of Pathophysiology, Institute of Basic Medical Science, PLA General Hospital, Beijing 100853, China

A R T I C LE I N FO

A B S T R A C T

Keywords: Chinese materia medica Cardiomyocyte Apoptosis Apoptotic pathway Intracellular signal transduction

Apoptosis is an evolutionarily conserved suicide process. It plays critical roles in the development and homeostasis of cardiac tissues. However, excessively stimulated apoptotic activity induced by a myriad of deleterious stimuli can result in too much cardiomyocyte death. The regenerative potential of the adult cardiomyocytes is limited. The cardiomyocyte loss cannot be compensated by efficient cell proliferation. It inevitably leads to various heart diseases. Therefore, the inhibition of cardiomyocyte apoptosis is an important therapeutic strategy for heart diseases. Chinese materia medica (CMM) has more than 2000 years of history and provides effective adjuvant therapeutic strategies for heart disease at the clinical level. The mechanisms underlying the beneficial effects of CMM on heart diseases have been a major focus of recent research. Interestingly, it has been demonstrated that CMM can up-regulate the levels of anti-apoptotic proteins and down-regulate the levels of proapoptotic proteins to inhibit apoptotic activity, thereby suppressing cardiomyocyte apoptosis in response to harmful stimuli. The inhibitory effects of CMM on apoptotic activity are mediated by the transduction of intracellular signaling. In this review, we summarize and discuss current findings on the roles and mechanisms of CMM in cardiomyocyte apoptosis.

1. Introduction Apoptosis, also known as programmed cell death, is an evolutionarily conserved suicide process that exerts pivotal roles in embryonic development and in the maintenance of tissue homeostasis. It is triggered by three central pathways including the extrinsic (death receptor) apoptotic pathway, intrinsic (mitochondrial) apoptotic pathway, and endoplasmic reticulum (ER) stress-related apoptotic pathway [1–4]. Intracellular signal transduction mediates the process [5–7]. Dysregulation of apoptosis, resulting in either too little or too much cell death, has been implicated in human disease [3]. In the heart, apoptosis is essential for shaping cardiac structures during early morphogenesis and for regulating the growth of differentiated cardiac tissues at later developmental stages [8,9]. The myocardium is comprised of cardiomyocytes with limited proliferation ability. Various stress stimuli induce excessive apoptosis of cardiomyocytes [3,10]. Since the cardiomyocyte loss cannot be compensated by efficient cell proliferation, abnormal induction of apoptosis in cardiomyocytes may lead to heart diseases. Therefore, the inhibition of cardiomyocyte apoptosis is an important therapeutic strategy for heart diseases. With more than 2000 years of history, Chinese material medica (CMM) has formed a unique system to cure illness. According to the ⁎

theory of traditional Chinese medicine, the occurrence of illness is due to the imbalance of Yin and Yang (two opposing forces of energy) and the disturbance of Qi and blood. CMM aims to restore the harmony of Yin and Yang and regulate Qi and blood. Some clinical trials have proven that CMM as adjuvant treatment is effective for patients suffering from heart diseases, including chronic heart failure, chronic stable angina, unstable angina, or non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention, acute myocardial infarction, and so on [11–13]. For example, Shexiang Baoxin Pill has been extensively used for the prevention and treatment of unstable angina, myocardial infarction, and heart failure [14–16]. On a background of standard treatment, Qili Qiangxin capsules further reduce the levels of NT-proBNP, ameliorate exercise tolerance and the NYHA functional class in patients with chronic heart failure [17]. Berberine is proved to lower serum levels of cholesterol, triglycerides and LDL-c in hypercholesterolemic people [18]. These findings suggest that CMM has the ability to further improve the prognosis of patients with heart diseases. Notably, in addition to CMM, conventional Western medicines are provided to all of the participants throughout the trials. Therefore, these clinical trials suggest that CMM has adjuvant effects on patients with heart diseases. Effective adjuvant treatment of CMM for heart diseases has

Corresponding author. E-mail address: [email protected] (Y. Li).

https://doi.org/10.1016/j.biopha.2019.109372 Received 23 April 2019; Received in revised form 19 August 2019; Accepted 22 August 2019 0753-3322/ © 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

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of doxorubicin on tumor volume or the induction of tumor cell apoptosis [45]. In addition, adriamycin-induced cardiomyocyte apoptosis is decreased by tanshinone II [46]. (2) The tonifying Qi herb group which is used to treat diseases that involve a deficit in “qi.” Ten active components (Panax quinquefolium saponin, Pseudostellaria heterophylla saponin, ginsenoside Rb1, echinatin, licochalcone C, astragalin, astragaloside IV, gypenosides, calycosin and astragalus polysaccharides) are extracted from tonifying Qi herbs. These active components can inhibit cardiomyocyte apoptosis induced by ischemia [47–49], I/R [50–56], H2O2 [23,57] and high glucose [58]. Also, astragaloside IV is able to decrease cardiomyocyte apoptosis upon doxorubicin insults [59]. (3) The Qingre Jiedu herb group which removes heat and toxic materials. Ten active components (terpene glycoside, hirsutine, apigenin, geniposide, hyperoside, coptisine, cynaroside, baicalin, 6-Gingerol and tournefolic acid B) can protect cardiomyocytes from apoptosis in response to ischemia [60,61], I/R [27,62–68], H2O2 [69,70]. Two active components including naringenin-7-O-glucoside, and Honokiol are able to inhibit doxorubicin-induced cardiomyocyte apoptosis [71,72]. (4) The tonifying Yin herb group is used to treat Yin deficiencies. Polysaccharides and Ophiopogonin D are capable of attenuating cardiomyocyte apoptosis upon H2O2 [73] and angiotensin II [74] insults. (5) The tonifying Yang herb group is used to treat Yang deficits. Higenamine and puerarin can inhibit I/R-induced cardiomyocyte apoptosis [75,76]. (6) The tonifying kidney herb group is used to treat kidney weakness. Both icaritin and icariin are extracted from Epimedium brevicornu Maxim. They can suppress cardiomyocyte apoptosis induced by I/R [77], H2O2 [78], and isoproterenol [79]. (7) In the supplementary blood herb group, only jujuboside A is proven to decrease cardiomyocyte apoptosis after exposure to norepinephrine [80].

prompted studies of the molecular mechanisms by which CMM interferes with heart diseases. Many studies have focused on the direct effects of CMM on cardiomyocyte apoptosis and the underlying mechanisms using in vitro cell models and/or in vivo animal models. Frequent keywords for these studies include CMM types and models, cardiomyocyte/myocardium, and apoptosis. The keywords also include key molecules involved in the disease mechanisms. In this review, we summarize current knowledge and highlight recent advances in our understanding of the effects of CMM on cardiomyocyte apoptosis induced by various harmful stresses. Based on these previous findings, we address how CMM exerts the inhibitory effects on cardiomyocyte apoptosis. 2. Overview of the effects of CMM on cardiomyocyte apoptosis under various stress conditions We employed PubMed to search the following terms: CMM and cardiomyocyte apoptosis or traditional Chinese medicine and cardiomyocyte apoptosis or herb and cardiomyocyte apoptosis or CMM/traditional Chinese medicine/herb and heart and apoptosis. According to the results of the PubMed research, it has been demonstrated that CMM effectively reduces cardiomyocyte apoptosis, including evidence for the effects of 43 active components (Table 1), 18 compound CMM preparations, and 9 single herbs (Table 2). These data suggest that CMM has beneficial effects on cardiomyocyte apoptosis. Based on the main indications in traditional Chinese medicine, we group the above CMM and summarize their effects on cardiomyocyte apoptosis. 2.1. The effects of CMM active components on cardiomyocyte apoptosis The 46 active components can be divided into 7 groups (Table 1). (1) The Huoxue Huayu herb group which promotes blood circulation and reduces blood stasis. The 17 active components isolated from Huoxue Huayu herbs are reported to inhibit cardiomyocyte apoptosis under heart diseases and drug treatments. Heart diseases are induced by various harmful stresses including ischemia, ischemia/reperfusion (I/ R), oxidative stress, angiotensin II/overload-induced myocardial hypertrophy, high glucose and so on. Under ischemia [19,20], I/R [21–29], and H2O2 [30] conditions, 10 active components (i.e., tanshinone IIA, polydatin, resveratrol, salidroside, salvianolic acid A, myricetin, myricitrin, notoginsenoside R1, orientin, and isorhamnetin) reduce cardiomyocyte apoptosis and myocardial infract size, thereby improving cardiac function. In heart failure models, it is reported that liguzinediol can prevent cardiomyocyte apoptosis and ameliorate cardiac dysfunction [31]. Angiotensin II or pressure overload can induce myocardial hypertrophy. Three active components (tanshinone IIA, Panax notoginseng saponins, and hydroxysafflor yellow A) inhibit cardiomyocyte apoptosis upon angiotensin II or pressure overload stimulation [32–34]. Simultaneously, myocardial fibrosis is improved. Myricitrin and Aralia taibaiensis saponins are thought to inhibit cardiomyocyte apoptosis induced by high glucose, thus protecting against diabetic cardiomyopathy [35,36]. In addition to inhibiting cardiomyocyte apoptosis induced by various stresses, CMM can also alleviate some drug treatment-induced cardiotoxicity by decreasing cardiomyocyte apoptosis. Doxorubicin is one of the most widely used anticancer drugs. However, its potential usage in long term is largely limited due to doxorubicin-induced cardiomyopathy, and in some cases, is reported to be fatal [37–39]. Multiple mechanisms underlying doxorubicin-induced irreversible myocardial injures have been proposed. Most of these mechanisms ultimately result in cardiomyocyte apoptosis [40]. Therefore, the inhibition of cardiomyocyte apoptosis is a fundamental strategy for the treatment of myocardial injures induced by doxorubicin. Studies have indicated that tanshinone IIA, ginkgolide B, Ginkgo biloba extract 761, Herba leonurine and salvianolic acid B are able to reduce doxorubicin-induced apoptosis and improve cardiomyocyte functions [41–44]. Intriguingly, CMM does not interfere with the effects

2.2. The effects of compound CMM preparations on cardiomyocyte apoptosis Twenty compound CMM preparations can be classified into five groups (Table 2). (1) The Huoxue Huayu herb group. The group includes Danshen dripping pills [81], Guanxin II [82], Guanxin Shutong capsules [83], Xue Sai Tong soft capsules [84], Hong Jing Tian injection [85], Huang Zhi oral liquid [86], Xue Fu Zhu Yu decoction [87], and Danhong injection [88,89]. These compound CMM preparations can inhibit cardiomyocyte apoptosis after exposure to ischemia [81–84], I/ R [85–88], and H2O2 [88,89]. (2) The tonifying Qi and Huoxue herb group. Seven compound CMM preparations belong to this group including Tong Xin Luo [90], Guanxintai [91], Qiliqiangxin capsules [92–94], Bu Yang Huan Wu decoction [95], Shen Yuan Dan [96], Shuang Shen Ning Xin [97] and Qishen Yiqi dropping pill [98]. Under ischemic conditions, cardiomyocyte apoptosis is reduced by Tong Xin Luo [90], Guanxintai [91], and Qiliqiangxin capsules [93]. Additionally, in ischemia and pressure overload models, Qiliqiangxin capsules can decrease cardiomyocyte apoptosis [92,94]. Bu Yang Huan Wu decoction, Shen Yuan Dan, and Shuang Shen Ning Xin prevent cardiomyocyte apoptosis induced by I/R [95–97]. Also, Qishen Yiqi dropping pill has the ability to ameliorate doxorubicin-induced cardiomyocyte apoptosis [98] (3) In the tonifying Qi herb group, Sheng Mai San and Xin Fu Li granules are used for tonifying Qi. Sheng Mai San suppresses cardiomyocyte apoptosis induced by ischemia [99]. Xin Fu Li granules reduce doxorubicin or adriamycin -induced cardiotoxicity by inhibiting cardiomyocyte apoptosis [100,101]. (4) In the tonifying Qi-Yang herb group, Shen Fu injection and Guizhi Gancao Decoction have the inhibitory roles in cardiomyocyte apoptosis upon I/R [102,103]. (5) In the supplementary blood herb group, San Yang Xue Dai can lower cardiomyocyte apoptosis in response to doxorubicin treatment [45]. 2.3. The effects of single herbs on cardiomyocyte apoptosis Nine single herbs can be divided into five groups (Table 2). (1) In 2

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Y. Li and X. Liu

Table 1 Inhibitory effects of active components of CMM on cardiomyocyte apoptosis and underlying mechanisms under various stresses. Groups based on main indications of TCM

Active components of CMM

Origins

Signaling pathways

Apoptosis / Apoptotic pathways

Stresses

Refs.

Huoxue Huayu herb group

Tanshinone IIA

Salvia miltiorrhiza

ERK activation PI3K/AKT activation

↓/Intrinsic pathway ER stress pathway

[33]

Polydatin

Polygonum cuspidatum

Rho/ROCK inhibition

↓/—

Resveratrol Salidroside Salvianolic acid A

Polygonum cuspidatum Rhodiola rosea L Salvia miltiorrhiza

↓/Intrinsic pathway ↓/— ↓/Intrinsic pathway

Myricetin Myricitrin

MyricarubraSieb.etZucc MyricarubraSieb.etZucc

AKT activation — ERK activation JNK inhibiton mTOR activation p38 inhibition AKT activation

Ischemia Ang II DOX ADM Ischemia I/R I/R Ischemia I/R

Notoginsenoside R1

Panax notoginseng

Orientin

Polygonum orientale L

Isorhamnetin

Hippophae rhamnoides L.

JNK inhibition Rho/ROCK inhibition PI3K/AKT/mTOR activation ERK inhibition

Liguzinediol Panax notoginseng saponins Hydroxysafflor yellow A Aralia taibaiensis Saponins Ginkgo biloba extract 761 Herba leonurine Salvianolic acid B

Ligusticum wallichii Franch Panax notoginseng Carthamus tinctorius L. Aralia taibaiensis Ginkgo biloba Herba Leonuri Salvia miltiorrhiza

NFκB inhibition — — — — Ca2+ overload↓ Ca2+ overload↓

Panax quinquefolium saponin Pseudostellaria heterophylla Saponin Ginsenoside Rb1 Echinatin licochalcone C Astragalin

Panax quinquefolium

—

Pseudostellaria heterophylla

—

Panax ginseng C. A. Mey Radix Glycyrrhiza Glycyrrhiza uralensis Fisch Radix astragali

Rho inhibition — — —

Astragaloside IV

Radix astragali

—

Gypenosides Calycosin Astragalus polysaccharides Terpene glycoside

Gynostemma pentaphyllum Radix astragali Astragalus membranaceus Radix paeoniae rubra

Hirsutine

Uncaria rhynchophylla

— AKT activation — PI3K/AKT/mTOR activation —

Apigenin Geniposide

Apium graveolens L. var. dulceDC Gardenia jasminoides J

Hyperoside Coptisine Cynaroside Baicalin Naringenin-7-O-glucoside Honokiol 6-Gingerol

Hypericum perforatum L. Rhizoma coptidis Lonicera japonica Thunb Scutellaria baicalensis Georgi Dracocephalum rupestre Hance Magnolia officinalis ginger

Tournefolic acid B Polysaccharide Ophiopogonin D Higenamine Puerarin Icaritin Icariin

Clinopodium chinense Dendrobium officinale Radix ophiopogonis Aconite Radix Puerariae Epimedium brevicornu Maxim Epimedium brevicornu Maxim

Jujuboside A

Zizyphus jujuba

Tonifying Qi herb

Qingre Jiedu herb

Tonifying Yin herb Tonifying Yang herb Tonifying kidney herb

Tonifying blood herb

p38 inhibition PI3K/AKT activation Ca2+overload↓ — — JNK inhibition — — — JNK inhibition NFκB inhibition JNK inhibition PI3K/AKT activation Ca2+ overload↓ PI3K/AKT activation — PI3K/AKT activation ERK activation Ca2+overload↓ ERK activation p38 inhibition JNK inhibition AKT activation

↓/— ↓/Intrinsic pathway

[20] [24] [29] [19] [21] [22]

↓/ER stress pathway

I/R I/R HG I/R

↓/

I/R

[25] [26] [36] [27] [143] [28]

↓/Intrinsic pathway no effect on extrinsic pathway ↓/Intrinsic pathway ↓/— ↓/ER stress pathway ↓/— ↓/Intrinsic pathway ↓/Intrinsic pathway ↓/Intrinsic pathway ER stress pathway ↓/Intrinsic pathway ER stress pathway ↓/—

H2O2

[30]

DOX Ang II Pressure overload HG DOX DOX DOX

[31] [32] [34] [35] [43] [44] [41]

Ischemia I/R Ischemia

[47] [54] [48]

↓/— ↓/TNF-α↓ ↓/TNF-α↓ ↓/TNF-α↓ Intrinsic pathway ↓/Intrinsic pathway TNF-α↓ — ↓/Intrinsic pathway ↓/— ↓/ER stress pathway ↓/Intrinsic pathway

I/R I/R I/R I/R

[50] [53] [56] [52]

I/R H2O2 DOX I/R H2O2 HG Ischemia

[51] [33] [59] [55] [23] [58] [60]

↓/Intrinsic pathway Extrinsic pathway ↓/Intrinsic pathway ↓/Intrinsic pathway

Ischemia

[61]

I/R I/R

[62] [65]

↓/Intrinsic ↓/— ↓/Intrinsic ↓/Intrinsic ↓/Intrinsic ↓/— ↓/Intrinsic

I/R I/R H2O2 H2O2 DOX DOX I/R

[64] [63] [70] [69] [71] [72] [67]

I/R H2O2 Ang II I/R I/R I/R H2O2 Isoproterenol NE

[68] [73] [74] [76] [75] [77] [78] [79] [80]

pathway pathway pathway pathway pathway

↓/ER stress pathway ↓/Intrinsic pathway ↓/ER stress pathway ↓/Intrinsic pathway ↓/Intrinsic pathway ↓/TNF-α↓ ↓/Intrinsic pathway TNF-α↓ ↓/ Intrinsic pathway

ADM: Adriamycin; Ang II: Angiotensin II; CMM: Chinese materia medica; DOX: Doxorubicin; HG: High glucose; I/R: Ischemia/reperfusion; LPS: Lipopolysaccharide; Norepinephrine: NE; TCM: traditional Chinese medicine. 3

Huoxue Huayu herb

Compound CMM preparations

4

Supplementing blood herb

Tonifying Qi-Yang herb

Tonifying Qi herb

Tonifying Qi and Huoxue herb

Groups based on main indications of TCM

Classification

Ischemia I/R

I/R

↓/— ↓/— ↓/Intrinsic pathway

Ca2+ overload ↓ —

Ischemia

↓/—

↓/—

ERK activation PI3K/ AKT activation

p38 inhibition

Shen Fu injection Guizhi Gancao Decoction San Yang Xue Dai

Qishen Yiqi Dropping Pill Sheng Mai San Xin Fu Li granule

Shuang Shen Ning Xin

Bu Yang Huan Wu decoction Shen Yuan Dan

Qiliqiangxin capsule

Guanxintai

Tong Xin Luo

Sanguis draconis, Radix et rhizoma notoginseng, Radix et rhizoma glycyrrhizae, Radix angelicae sinensis, Ginger, Rhizoma Dioscoreae, Poria cocos, and Fructus Amomi

Panax ginseng, Fructus schisandrae, Radix ophiopogonis Radix astragali, Radix ginseng, Salvia miltiorrhiza, Scirpus fluviatilis, Rhizoma Alismatis, Angelica sinensis, Semen lepidii, Fructus chaenomelis, Semen arecae, Ophiopogon japonicus Radix Ginseng and Radix Aconiti Carmichaeli Ramulus Cinnamomi and Radix Glycyrrhizae

Radix ginseng, Buthus martensi, Hirudo, Eupolyphaga seu steleophaga, Scolopendra subspinipes, Periostracum cicadae, Radix paeoniae rubra, Semen ziziphi spinosae, Lignum dalbergiae odoriferae, Lignum santali albi, Borneolum syntheticum Ginseng, Astragalus, Rehmannia, Ophiopogon root, Schisandra chinensis, Frankincense, Myrrh, Angelica, Rhizoma Chuanxiong, Fructus liquidambaris, Radix cyathulae, Salvia miltiorrhiza, Acorusgramineus, Herba leonurine Aradix, Ginseng radix et rhizoma, Aconiti lateralis radix preparata, Salvia miltiorrhiza, Semen descurainiae lepidii, alismatis rhizoma, Polygonati odorati rhizoma, Cinnamomi ramulus, Carthami flos, Periploca cortex, Citri reticulatae pericarpium Radix Astragali, Radix Angelicae Sinensis, Radix paeoniae Rubra, Rhizoma Ligustici Chuanxiong, Flos Carthami, Semen Persicae and Lumbricus Salvia miltiorrhiza, Astragalus membranaceus Bge, root of Pilose Asiabell, Radix Scrophulariae, Hirudo nipponica, Lumbricus, Eupolyphagasinensis, Rhizoma Corydalis Ginseng Radix et Rhizoma, Salviae miltiorrhizae Radix et Rhizoma, and Corydalis Rhizoma Radix astragali, Salvia miltiorrhiza, Panax notoginseseng, Dalbergia odorifera

I/R H2O2 Ischemia

↓/Intrinsic pathway

Ca2+ overload↓

Danhong injection

mTOR inhibition

Semen persicae, Safflower, Angelica, Rhizoma ligustici wallichii, Rehmanniae, Radix paeoniae rubra, Achyranthes, Bupleurum, Fructus aurantii immaturus, Platycodon grandiflorum, Liquorice. Radix Salviae Miltiorrhizae, Flos Carthami

Xue Fu Zhu Yu decoction

↓/Intrinsic pathway ↓/Intrinsic pathway

— —

↓/Intrinsic pathway ↓/Intrinsic pathway

↓/Intrinsic pathway ↓/Intrinsic pathway TNF-α↓ ↓/—

— NFκB inhibition —

Ca —

overload ↓ 2+

↓/Intrinsic pathway PI3K/ AKT activation

[45]

[102] [103]

[99] [100] [101]

[98]

[97]

[96]

[95]

[93] [92] [94]

[91]

[88] [89] [90]

[87]

[86]

[85]

[84]

[83]

[81] [82]

Refs.

(continued on next page)

DOX

I/R I/R

Ischemia ADM DOX

DOX

I/R

I/R

↓/—

—

—

Ischemia Ischemia Pressure overload I/R

↓/Intrinsic pathway ↓/— ↓/— AKT activation

I/R

↓/Intrinsic pathway Extrinsic pathway ↓/—

leech, rhubarb, and Fructus arctii

Huang Zhi oral liquid

Ischemia

Ischemia Ischemia

↓/— ↓/Intrinsic pathway

— AKT activation

Stresses

Apoptosis / Apoptotic pathways

Signaling pathways

AKT /mTOR activation ERK activation —

Salvia miltiorrhiza, Radix Notoginseng, Borneolum Salvia miltiorrhiza, Carthamus tinctorius L., Paeonia lactiflora Pall., Ligusticum wallichii Hort. Dalbergia odorifera T. Chen Choerospondias axillaris, Salvia miltiorrhiza, Syzigium aromaticum, Dryobalanops, Tabaschir Panax notoginseng saponins

Ingredients

Salidroside, Tyrosol, Rosavin, Rozarin, Rosin

Guanxin Shutong capsule Xue Sai Tong soft capsule Hong Jing Tian injection

Danshen dripping pill Guanxin II

Names

Table 2 Inhibitory effects of compound CMM preparations and single herbs on cardiomyocyte apoptosis and underlying mechanisms under various stresses.

Y. Li and X. Liu

Biomedicine & Pharmacotherapy 118 (2019) 109372

Biomedicine & Pharmacotherapy 118 (2019) 109372 [107] [108] [109] [110] [111] [112] Ang II DNR I/R I/R D-gal Ang II Supplementing blood herb

Qingre Jiedu herb Tonifying kidney herb

Tonifying Qi herb

Platycodon grandiflorum Astragalus membranaceus Dracocephalum moldavica Herba Cistanches Alpinate Oxyphyllae Fructus Radix Angelicae Sinensis

Ca2+ overload↓ JNK inhibition NFκB inhibition JNK inhibition — — — PI3K/ AKT activation PI3K/ AKT activation Salvia miltiorrhiza Carthamus tinctorius L.

Radix paeoniae rubra Single herb

Huoxue Huayu herb

Ingredients Names Groups based on main indications of TCM Classification

Table 2 (continued)

ADM: Adriamycin; Ang II: Angiotensin II; CMM: Chinese materia medica; DNR: Daunorubicin; D-gal: D-galactose; DOX: Doxorubicin; HG: High glucose; I/R: Ischemia/reperfusion; LPS: Lipopolysaccharide; Norepinephrine: NE; TCM: traditional Chinese medicine.

[105] [106] I/R LPS

[104]

↓/Intrinsic pathway no effect on extrinsic pathway ↓/— ↓/Intrinsic pathway Extrinsic pathway ↓/— ↓/— ↓/— ↓/— ↓/Intrinsic pathway ↓/Intrinsic pathway —

Ischemia

Apoptosis / Apoptotic pathways Signaling pathways

Stresses

Refs.

Y. Li and X. Liu

the Huoxue Huayu herb group, Radix Paeoniae Rubra, Salvia miltiorrhiza, and Carthamus tinctorius L. inhibit cardiomyocyte apoptosis induced respectively by ischemia [104], I/R [105], and lipopolysaccharides [106]. (2) In the tonifying Qi herb group, Platycodon grandiflorum can reduce angiotensin II-induced cardiomyocyte apoptosis [107]. Daunorubicin is antitumor antibiotics. Cardiotoxicity is serious side effect of daunorubicin that limits its widespread use in clinic. This cardiotoxicity is caused by excessive apoptosis of cardiomyocytes. Astragalus membranaceus is able to attenuate daunorubicininduced cardiomyocyte apoptosis [108]. (3) In the Qingre Jiedu herb group, Dracocephalum moldavica decreases cardiomyocyte apoptosis in response to I/R [109]. (4) In the tonifying kidney herb group, I/Rinduced cardiomyocyte apoptosis is blocked by Herba Cistanches [110]. D-galactose can promote heart aging by stimulating cardiomyocyte apoptosis. It has been demonstrated that Alpinate Oxyphyllae Fructus inhibits cardiomyocyte apoptosis in response to D-galactose [111]. (5) In the supplementary blood herb group, Radix Angelicae Sinensis has the ability to decrease cardiomyocyte apoptosis upon angiotensin II stimulation [112]. 2.4. The toxicity effects of CMM on cardiomyocytes Despite evidence for a protective effect of CMM against stress-induced cardiomyocyte apoptosis, not all CMM properties are of beneficial to cardiomyocytes. Some studies have reported that CMM has cardiotoxicity (Table 3). Triptolide, a major active ingredient derived from Tripterygium wilfordii Hook f., possesses various biological activities. However, owing to its toxicity, the clinical applications of triptolide are limited. Triptolide induces cardiomyocyte apoptosis in studies of in vitro and in vivo models [113–115]. Aconitum carmichaelii is used for the treatment of pain and inflammation in the joints. Diterpenoid Alkaloid from aconitum carmichaelii is used for the treatment of pain and inflammation in the joints. However, it was proved that diterpenoid alkaloid induces cardiomyocyte apoptosis [116,117]. Evodiamine from evodia rutaecarpa is reported to increase cardiomyocyte death and induce cardiac malfunction [118]. Ephedra is an herb that suppresses the appetite and stimulates the sympathetic nervous system as well as cardiac performance, but it has serious cardiotoxicity. Its cardiotoxicity is related to cardiomyocyte apoptosis [119]. These results emphasize the need for additional studies of the cardiotoxicity of CMM and the related mechanisms. 3. CMM inhibits the trigger of apoptosis pathways Apoptosis is triggered by three main pathways including the extrinsic (death receptor) apoptotic pathway, the intrinsic (mitochondrial) apoptotic pathway, and the ER stress-related apoptotic pathway. These three apoptosis pathways can be regulated by CMM (Tables 1, 2 and Fig. 1). With respect to the extrinsic apoptotic pathway, the effects of 11 CMMs, including 8 active components, 1 compound CMM preparation, and 2 single herbs have been studied. Most of these studies have focused on the roles of CMM in the intrinsic apoptotic pathway, for which 44 CMM have been investigated, including 30 active components, 10 compound CMM preparations, and 4 single herbs. For the ER stress-related apoptotic pathway, only 6 active components have been evaluated. 3.1. Extrinsic apoptotic pathway The extrinsic apoptotic pathway is initiated by signaling from the cell-surface death receptors triggered by death ligands. The major death receptors include CD95 (also named Fas/APO-1), TNF-R1, TRAIL receptor 1 (TRAIL-R1), TRAIL-R2, DR3, and DR6.2 [120]. They can bind to proinflammatory ligands, such as FasL, TNF- and so on. Receptor–ligand binging can initiate the formation of a multiprotein complex, referred to as the death-inducing signaling complex (DISC). 5

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Table 3 The toxicity effects of CMM on cardiomyocytes. Name

Catalogy

Origins

Signaling pathways

Apoptotic pathways

Cardiotoxicity

Refs.

Triptolide Diterpenoid Alkaloid

Active component Active component

— —

Intrinsic pathway Intrinsic pathway

Apoptosis↑ Apoptosis↑

[113–115] [116,117]

Evodiamine

Active component

Tripterygium wilfordii Hook f. Aconitum carmichaelii/Aconitum leucostomum Worosch Evodia rutaecarpa

—

—

[118]

Ephedra

Single herb

—

—

Intrinsic pathway

Cell death ↑ Cardiac malfunction Apoptosis↑

[119]

CMM: Chinese materia medica.

extrinsic pathway by CMM. These results suggest that CMM can inhibit cardiomyocyte apoptosis by blocking the extrinsic apoptotic pathway. Notably, Sun et al. [30] reported that under H2O2 conditions, isorhamnetin has no obvious inhibitory effects on the extrinsic pathway, as determined by the lack of caspase-8 activation along with a lack of changes in Fas and TNFR1 mRNA levels. Similarly, cleaved caspase-8 is not significantly altered following jujuboside A pretreatment in cardiomyocytes exposed to norepinephrine [80]. It seems that the inhibitory effect of some CMM on cardiomyocyte apoptosis is not through the extrinsic apoptotic pathway.

DISC formation induces the activation of caspases 8/10, thereby activating caspases 3/6/7 and triggering apoptosis [4]. Some studies have demonstrated that CMM can inhibit cardiomyocyte apoptosis via the extrinsic pathway [61,86,104,106]. Carthamus tinctorius L., an individual herb, and Huangzhi oral liquid, a compound CMM preparation, belong to the Huoxue Huayu herb group. Tien et al. [106] found that Carthamus tinctorius L. protects against lipopolysaccharide-induced cardiomyocyte apoptosis via the inhibition of TNF-α up-regulation and caspase-8 activation. In a myocardial I/R injury model, Ran et al. [86] found that the Huangzhi oral liquid down-regulates Fas expression. Hirsutine, which removes heat and toxic materials, is the active component of Uncaria rhynchophylla. It can reduce Fas expression in cardiomyocytes upon hypoxia insult [61]. In addition to the above findings, in the tonifying Qi herb group, 3 active components including Echinatin, Licochalcone C and Astragalin are shown to decrease TNF-α level in cardiomyocytes upon I/R stimulation [52,53,56]. The active component Astragaloside IV can suppress the increase in TNF-α induced by H2O2 [57]. Additionally, 2 active components (Icaritin and Icariin) belonging to the tonifying kidney herb group can reduce TNF-α production respectively during I/R [77] or isoproterenol [79]. Unfortunately, these studies do not further explore whether there is a direct link between a reduction in TNF-α and the inhibition of the

3.2. Intrinsic apoptotic pathway In total, 30 of 43 active components, 10 of 18 compound CMM preparations, and 4 of 9 single herbs are known to suppress the intrinsic pathway (Tables 1 and 2). The initiation of apoptosis by the intrinsic pathway requires the release of mitochondrial death factors, including cytochrome c, second mitochondria-derived activator of caspase (SMAC)/DIABLO, and so on. The release of these factors is usually associated with an increase in mitochondrial outer membrane permeabilization (MOMP) [121,122]. As a direct result of increased MOMP, the dissipation of mitochondrial membrane potential (MMP) is

Fig. 1. The main apoptotic pathways affected by Chinese materia medica (CMM). (A) Extrinsic apoptotic pathway. CMM down-regulates TNF- and Fas expression to inhibit DISC information, thus ultimately suppressing caspase-8 activation; (2) Intrinsic apoptotic pathway. The up-regulation of Bcl-2 expression and the downregulation of Bax expression by CMM inhibit the increase of MOMP (MMP collapse as a direct result of increased MOMP), decrease the release of mitochondrial death factors including cytochrome c and SMAC/ /DIABLO, thereby preventing caspase-9 activation; (3) ER stress apoptotic pathway. The protein levels of ER stressresponsive proteins including GRP78, PERK, ATF6 and IRE are attenuated by CMM, which suppresses CHOP expression and caspase-12 activation. DISC: deathinducing signaling complex; MOMP: mitochondrial outer membrane permeabilization; MMP: mitochondrial membrane potential; SMAC/DIABLO: second mitochondria-derived activator of caspase; GRP78: glucose regulated protein 78; PERK: protein kinase R-like endoplasmic reticulum kinase; ATF6: activating transcription factor 6; IRE1: inositol-requiring kinase 1; ER: endoplasmic reticulum. 6

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cardiomyocyte apoptosis. Five active components and two compound CMM preparations are known to regulate ERK activity and thereby to inhibit cardiomyocyte apoptosis. As shown in Fig. 2, the role of CMM in the ERK pathway is controversial. Studies of four active components and two compound CMM preparations suggest that CMM inhibits cardiomyocyte apoptosis by the activation of the ERK pathway [78,80,90]. Jujuboside A promotes the activation of ERK in norepinephrine-treated cells [80]. Icariin up-regulates the expression of phosphorylated-ERK in cardiomyocytes exposed to H2O2 [78]. Tongxinluo and Hong Jing Tian injection increase the phosphorylation of ERK in ischemia or I/R hearts [90]. However, another study has shown that CMM prevents cardiomyocyte apoptosis via the inhibition of the ERK pathway [30]. A reduction in ERK activity is required for the inhibitory effect of isorhamnetin on H2O2-induced cardiomyocyte apoptosis [30]. The activation of ERK is associated with survival pathways against proapoptotic stimuli and with the promotion of the apoptotic program [131]. The role of ERK might be CMM-dependent. Additionally, p38 and JNK mediate the inhibitory effect of CMM on cardiomyocyte apoptosis. Three active components and one compound CMM preparation are known to inhibit p38 activation. Myricetin and apigenin can reduce the level of phosphorylated-p38 in cardiomyocytes exposed to I/R [25,62], and jujuboside A can decrease the level of phosphorylated-p38 in cardiomyocytes upon norepinephrine stress [80]. Guanxintai prevents p38 activation in ischemia-treated cardiomyocytes [91]. Likewise, the activation of JNK by harmful stresses is abrogated by 4 active components (salvianolic acid A, notoginsenoside R1, cynaroside, and jujuboside A) and 2 single herbs (Carthamus tinctorius L. and Platycodon grandiflorum) [70,80,107].

commonly employed as an indicator of MOMP [123,124]. MOMP is regulated by the balance of anti- and pro-apoptotic Bcl-2 proteins [121]. Bcl-2 (an anti-apoptotic protein) and Bax (a pro-apoptotic protein) play pivotal roles in regulating MOMP. The ratio of Bax to Bcl-2 has a substantial influence on the ability of a cell to respond to apoptotic signals. Cells with high Bax/Bcl-2 ratios will be more sensitive to apoptotic stimuli than those with low Bax/Bcl-2 ratios [125]. As shown in Fig. 1, CMM down-regulates Bax at the mRNA and protein levels, and up-regulates Bcl-2 at the mRNA and protein levels [21,54], thus attenuating the Bax/Bcl-2 ratio [46,64,69,85,96]. Furthermore, it is reported that CMM increases MMP (indicating that MOMP is decreased) [30,55,97,99]. In CMM-pretreated cardiomyocytes, the levels of cytochrome c [33,42,70] and smac/Diablo [70] in the cytosol are downregulated, indicating that CMM has the ability to inhibit the release of mitochondrial death factors to the cytosol. These results suggest that CMM can inhibit the intrinsic pathway to protect cardiomyocytes from apoptosis. 3.3. ER stress-related apoptotic pathway ER stress refers to the ability of cells to respond to perturbations in ER function induced by harmful stimuli [126]. It is critical for cell survival, but chronic or severe ER stress can result in apoptosis [126]. The signal transduction in ER stress is mainly determined by three protein sensors on the ER membrane: protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring kinase 1 (IRE1), and activating transcription factor 6 (ATF6) [126–129]. Under physiological conditions, these three proteins are sequestrated in the ER lumen by binding to the ER chaperone glucose regulated protein 78 (GRP78), thereby keeping them inactive. Upon harmful stresses, these sensors would disassociate from GRP78 and be phosphorylated to initiate ER stress. However, when severe or sustained ER stress is induced, the apoptotic pathway is triggered by the activation of C/EBP homologous protein (CHOP) or caspase-12 [74,130]. Six active components inhibit the ER stress-related apoptotic pathway to impede cardiomyocyte apoptosis. Our results and those of other researchers (summarized in Fig. 1) indicate that CMM can decrease the protein levels of ER stressresponsive proteins GRP78, p-PERK, ATF6, and IRE, thereby inhibiting the expression of the ER stress-related apoptosis proteins CHOP, and caspase-12 [27,47,54]. These findings suggest that CMM decreases cardiomyocyte apoptosis via the ER stress-related apoptotic pathway. However, these studies have only focused on the expression changes of ER stress-responsive proteins. To clearly prove that CMM can inhibit the ER stress-related apoptotic pathway, further research is needed, including studies of the effects of interfering with the endogenous expression of the three sensor proteins.

4.2. Phosphatidylinositide 3 kinase (PI3K)-Akt-mammalian target of the rapamycin (mTOR)

Intracellular signal transduction plays important roles in mediating apoptosis. There are a large number of intracellular signal transduction pathways. To the best of our knowledge, the anti-apoptotic effects of CMM are mainly mediated by the following intracellular signal transduction pathways (Tables 1, 2, and Fig. 2).

PI3K/AKT/mTOR have central roles in signal transduction pathways and contribute to many aspects of cellular function. They are principal mediators of cell survival. The activation of PI3K/AKT/mTOR blocks apoptosis [132,133]. Accumulating evidence has shown that 12 active components, 6 compound CMM preparations, and 2 single herbs restrain cardiomyocyte apoptosis via the activation of PI3K/AKT/ mTOR (Fig. 2). Terpene glycoside elevates the expression of phosphorylated-AKT and phosphorylated-mTOR in cardiomyocytes subjected to isoproterenol. LY294002, a PI3K inhibitor, abrogates the inhibitory effect of terpene glycoside on the down-regulation of cleaved caspase-3 [60]. Under hypoxic conditions, CMM can activate PI3K/ AKT/mTOR, thereby inhibiting cardiomyocyte apoptosis [21,82,90,93]. I/R decreases the levels of phosphorylated-PI3K and phosphorylated-AKT, thus increasing cardiomyocyte apoptosis. In contrast, CMM up-regulates the expression of phosphorylated-PI3K and phosphorylated-AKT to reduce cardiomyocyte apoptosis [22,77,134]. The protective roles of CMM in cardiomyocytes are prevented by inhibitors of PI3K and AKT. According to these previous findings, CMM inhibits I/R-induced cardiomyocyte apoptosis by the activation of PI3K/AKT. In addition, CMM also prevents against cardiomyocyte apoptosis induced by other stimuli, including norepinephrine [80], oxidative stress [23], doxorubicin, angiotensin II [103], and high glucose [36] via the activation of PI3K/AKT.

4.1. Mitogen-activated protein kinases (MAPKs)

4.3. Ca2+-dependent signal transduction

MAPKs are serine-threonine protein kinases. They play a pivotal role in the transmission of intracellular signaling associated with numerous cellular activities, including apoptosis. The activation of MAPKs by various harmful stimuli ultimately contributes to either the inhibition or promotion of the apoptotic program [131]. MAPKs consist of three subfamilies: extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38. CMM can regulate the pathways of the three MAPK subfamilies to exert the inhibitory effects on

Ca2+ is a highly versatile intracellular signal that regulates many cellular processes, including apoptosis [135]. Ca2+ homeostasis is a prerequisite for cardiomyocyte survival. It is finely regulated by a set of proteins, including the L-type Ca2+ channel, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2) pump, and ryanodine receptor (RyR) channel [135,136]. The disruption of Ca2+ regulation can lead to intracellular Ca2+ overload. Increased intracellular Ca2+ activates a calmodulin-dependent kinase II (CaMK II) by calmodulin to induce

4. Intracellular signal transduction pathways mediating the inhibitory effects of CMM on cardiomyocyte apoptosis

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Fig. 2. Intracellular signal-transduction mediates the inhibitory role of Chinese materia medica (CMM) in cardiomyocyte apoptosis. (1) ERK inhibition/activation. The role of CMM in the ERK pathway is controversial. Activation or inhibition of ERK by CMM might be CMM-dependent. (2) JNK and p-38 inhibition. CMM can suppress the phosphorylation of JNK and p-38, thereby inhibiting JNK and/or p-38 pathways. (3) PI3K/AKT/mTOR activation. CMM up-regulates the phosphorylatory levels of PI3K, AKT and/or mTOR to activate PI3K/AKT/mTOR pathway. (4) Ca2+ overload. CMM can decrease the enhanced current of the LTCC, downregulate the expression of CaM and CaMKII, and up-regulate the expression of SERCA2, thus inhibiting Ca2+ overload. (5) NF-κB inhibition. CMM increases the expression of phosphorylated-NF-κB and reduces the DNA binding activity of NFκB to inhibit NF-κB pathway. (6) RhoA/ROCK inhibition. CMM decreases the expression of Rho and/or ROCK to prevent RhoA/ROCK pathway. Also, CMM can bind to RhoA to block RhoA activation. ERK: extracellular signal-regulated kinase; JNK: c-Jun NH2-terminal kinase; PI3K: phosphatidylinositide 3 kinases; mTOR: mammalian target of the rapamycin; LTCC: L-type Ca2+ channel; CaM: calmodulin; CaMK II: calmodulin-dependent kinase II; SERCA2: sarcoplasmic/endoplasmic reticulum Ca2+-ATPase; NF-kB: Nuclear factor-kB; Rho: Ras homolog gene family, member A; ROCK: Rho-associated coiled-coil containing protein kinase.

conditions [24]. Furthermore, surface plasmon resonance assays of the interaction of ginsenoside Rb1 with RhoA have shown that ginsenoside Rb1 can bind to RhoA [50]. These results suggest that ginsenoside Rb1 exerts anti-apoptotic effects by directly targeting RhoA.

apoptosis [135,137,138]. Numerous stresses can induce intracellular Ca2+ overload and ultimately cell death. Experimental studies have found that 6 active components, 3 compound CMM preparations, and one single herb are capable of preventing intracellular Ca2+ overload and consequently cardiomyocyte apoptosis [41,44,57]. Furthermore, the mechanism studies of the dampening effects of CMM on intracellular Ca2+ overload and cardiomyocyte apoptosis have demonstrated that CMM can decrease the enhanced current of the L-type Ca2+ channel, down-regulate the expression of CaM and CaMKII, and upregulate the expression of SERCA2 in cardiomyocytes [74,83,105].

5. Perspectives It is clear that CMM as adjuvant treatment is effective for patients with heart diseases and has a critical role in inhibiting cardiomyocyte apoptosis induced by various stresses. Also, it is clear the inhibitory roles of CMM in cardiomyocyte apoptosis are mediated via three apoptotic pathways. And intracellular signal transductions are involved in the process. Moreover, there are cross-talks within the apoptotic pathways, and between the apoptotic pathway and the intracellular signal-transduction. Looking ahead, there are several issues that need to be addressed. (1) The influences of CMM on signal transduction cross-talk are less well known. Future efforts to further dissect these complex relationships are needed. (2) Is CMM only active in conditions that involve cardiomyocyte apoptosis or is it active in other conditions, and why? To our knowledge, it has been demonstrated that CMM could also affect cardiomyocyte hypertrophy. This may be likely as some CMM affect e.g. ERK or P13 K/Akt/mTOR pathway. (3) What active components in single herbs contribute to the observed anti-apoptotic effects? (3) Although most of studies have suggested that CMM has beneficial effects on cardiomyocyte apoptosis and many clinical trials have proven that CMM is effective for patients suffering from heart diseases, some studies have found that CMM has pro-apoptotic roles in cardiomyocytes and cardiotoxicity. The toxicity and safety issues of CMM before clinical applications need to be further investigated. These future studies will be warranted to obtain a more complete understanding of the effects of CMM on cardiomyocyte apoptosis and to develop an efficient CMMbased therapeutics in heart diseases.

4.4. Nuclear factor -κB (NF-κB) NF-κB is a major signal-transduction pathway. It can be activated in response to various stimuli. Activated NF-κB binds to specific DNA sequences and regulates the transcription of target genes that mediate cell apoptosis [139]. Therefore, NF-κB is thought to orchestrate a cell survival pathway [139,140]. Two active components and one single herb are known to inhibit cardiomyocyte apoptosis by targeting the NF-κB pathway [31,106,141]. Pretreatment with astragaloside IV or liguzinediol significantly down-regulates the expression of NF-κB in cardiomyocytes, which is reduced by lipopolysaccharides or doxorubicin [31,141]. Additionally, Carthamus tinctorius L. prevents NF-κB phosphorylation, accompanied by a decrease in cardiomyocyte apoptosis [106]. 4.5. RhoA/Rho-associated coiled-coil containing protein kinase (ROCK) RhoA is a small GTPase belonging to the Rho family and plays a critical role in the regulation of apoptosis. ROCK is a major downstream effector of RhoA. The activation of the RhoA protein leads to the activation of ROCK. RhoA/ROCK activation is involved in cardiomyocyte apoptosis [50,142]. Three active components have the ability to inhibit RhoA/ROCK activation. Ginsenoside Rb1 and notoginsenoside R1 alleviate the up-regulation of RhoA and ROCK in cardiomyocytes induced by I/R [50,143]. ROCK activity is inhibited by polydatin under I/R 8

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Declaration of Competing Interest

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