Molecular machinery and interplay of apoptosis and autophagy in coronary heart disease

Journal of Molecular and Cellular Cardiology 136 (2019) 27–41

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Review article

Molecular machinery and interplay of apoptosis and autophagy in coronary heart disease Yan Dong1, Hengwen Chen1, Jialiang Gao1, Yongmei Liu, Jun Li, Jie Wang

T

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Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China

A R T I C LE I N FO

A B S T R A C T

Keywords: Coronary heart disease Apoptosis Autophagy Molecular machinery Interplay Therapeutic implication

Coronary heart disease (CHD) is a common heart disease and the leading cause of cardiovascular death. Apoptosis and autophagy are two forms of programmed cell deaths which participate in the pathogenesis, development and prognosis of CHD. They are activated by several different pathways respectively and can interact with each other through the Beclin 1-Bcl-2/Bcl-xL complex, mTOR, TRAIL, TNF-α, ER stress and nucleus p53 pathways. Excessive apoptosis can promote myocardial ischemia, ischemia/reperfusion (I/R) injury, postischemia cardiac remodeling and coronary atherosclerosis except for VSMC-induced atherosclerosis progress. In contrast, activated autophagy protects heart from myocardial ischemia injury and post-ischemia cardiac remodeling, but can exert controversial effects on I/R injury and coronary atherosclerosis. Therefore, considering the pathological significance and mechanisms of apoptosis and autophagy underlying CHD, therapeutic implication of targeting apoptosis and autophagy is obvious. Fortunately, some therapeutic drugs and pharmacologic compounds involving mTOR inhibitor and AMPK activator have been reported to regulate apoptosis and autophagy. Although recent studies are limited and insufficient, they have pointed out the complex interplay between apoptosis and autophagy and further provided treatment concept for CHD by balancing the switch between the two responses.

1. Introduction Coronary heart disease (CHD) is the leading cause contributing to cardiovascular death [1]. Its basic pathology involves the dysfunction of both vascular and myocardial processes which are induced and exacerbated by ischemia, hypoxia, oxidative stress, inflammation and apoptosis [2–4]. Recently, accumulating studies have reported the significance of autophagy in the pathogenesis of CHD [5–7]; and increasing researchers pay attentions on the interplay between autophagy and apoptosis [8–10]. Specifically, apoptosis is type 1 programmed cell death which involves early degradation of cytoskeleton but preservation of organelles until late phase; whereas autophagy belongs to type 2 cell death which has early collapse of organelles but preservation of cytoskeleton until last stage [11]. Apoptosis and autophagy are both adaptive responses and initially essential for cell growth, survival and homeostasis [12,13]. However, they can affect each other and act as important regulators for CHD [14], which has become the increasing subject of intensive investigations. Excessive apoptosis contributes to cell death invariably following ischemia, hypoxia, oxidative stress and endoplasmic reticulum (ER)

stress. In contrast, autophagy is a housekeeping process and plays dual roles in cell survival or death, which depends on the cellular context [13,15]. Under nutrient starvation, energy deprivation, oxidative stress and ER stress, autophagy is activated and considered as a pro-survival response [16]. Nevertheless, excessive or prolonged insult will lead to severe and deleterious upregulation of autophagy, resulting in cellular death [17]. Therefore, the mechanisms of apoptosis and autophagy underlying the occurrence and progress of CHD are complicated. However, recent evidences about the two responses and their interplay are not fully definded and understood. As a result, in this review article, we systematically summarized current understanding of molecular machinery and interplay of apoptosis and autophagy, and further pointed out their specific roles and therapeutic implications in myocardial ischemia, ischemia/reperfusion (I/R) injury, post-ischemia cardiac remodeling and coronary atherosclerosis. It's anticipated that this review would partly help to provide a treatment concept transforming from a single target to the balance of apoptosis and autophagy in the CHD therapy.

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Corresponding author. E-mail address: [email protected] (J. Wang). 1 These authors contributed equally to this work https://doi.org/10.1016/j.yjmcc.2019.09.001 Received 24 July 2019; Received in revised form 1 September 2019; Accepted 5 September 2019 Available online 07 September 2019 0022-2828/ © 2019 The Authors. Published by Elsevier Ltd. 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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Fig. 1. The molecular machinery of apoptosis in CHD. “→” represents promotion; “⊥” represents inhibition. “+P” stands for phosphorylation.

2. Molecular machinery of apoptosis

death domain. For example, after the binding of FasL to FasR or TNF-α to TNFR1, the fas-associated death domain (FADD) will be recruited and bind to the ligand-receptor complex [21]. Consecutively, FADD activates procaspase-8 and forms a death-inducing signaling complex (DISC) [22]. Finally, caspase-8 activated by DISC triggers caspases-3 and caspases-7 and thus induces the apoptotic cascade, leading to the execution phase of apoptosis [23].

There are three classic apoptotic signaling pathways: the extrinsic (death receptor) pathway, the intrinsic (mitochondrial) pathway and ER stress pathway (shown as Fig. 1). Through activating one or more above pathways, environmental stimuli can induce apoptosis. 2.1. The morphology of apoptosis

2.3. The intrinsic pathway-induced apoptosis

Apoptosis is a coordinated and self-killing process [10]. When apoptotic pathways are activated, cell begins to shrink. Morphological changes involving smaller size, denser cytoplasm, more tightly packed organelles and chromatin condensation are observed. Subsequently, plasma membrane blebbing occurs and tightly encloses the packed organelles with or without a nuclear fragment, promoting the formation of apoptotic bodies. Meanwhile, cytoskeletal and nuclear proteins are degraded and cleaved by caspases during the execution phase of apoptosis [18]. Finally, apoptotic bodies are phagocytosed by macrophages through recognizing the externalized phosphatidylserine on the outer leaflet of the bilayer [19]. The above apoptotic process involves many cell killing and engulfment proteins, among which caspases play the essential roles; especially, caspase-3 acts as the convergence of apoptosis-related signal pathways. Once activated, caspases usually activate other procaspases, promote protease cascade and thereby amplify the apoptotic signaling pathway irreversibly. At present, more than ten caspases have been reported and recognized as initiators (caspase-2,-8,-9,-10), executioners (caspase-3,-6,-7) [18,20] or other regulators (caspase-11,-12,-13,-14) in apoptosis.

The intrinsic signaling pathway is mitochondrial-initiated and can also trigger apoptosis. It's commonly activated by stimuli involving hypoxia, hyperthermia and the absence of growth factors. Those stimuli promote the opening of mitochondrial permeability transition pore, impede the mitochondrial transmembrane potential and thus accelerate the release of pro-apoptotic proteins involving Cytochrome c (Cyt c) and apoptosis-inducing factor (AIF) from the intermembrane space into the cytosol [24]. Cyt c can bind and activate Apaf-1 as well as procaspase-9 and subsequently result in caspase-9 activation which in turn promotes caspases-3 and caspases-7 [25,26]. However, AIF translocates to the nucleus and induces DNA fragmentation and chromatin condensation in a caspase-independent manner during the late phase of apoptosis [27]. Notably, the above mitochondrial-initiated events are regulated by B-cell lymphoma 2 (Bcl-2) family proteins [28] which are in the outer mitochondrial membrane. Bcl-2 family proteins control the permeability of mitochondrial membrane and then regulate the release of Cyt c. They can be functionally classified into pro-apoptotic and antiapoptotic proteins. The former includes Bad, Bax, Bak, Bid, Bim, Puma and BNIP3 [29]; while the latter contains Bcl-2, Bcl-x, Bcl-XL and BAG. Among those Bcl-2 family proteins, Bax can be upregulated by tumor suppressor protein p53 either in nucleus or mitochondria (np53 or mp53) [26,30]; while Bcl-2 or Bcl-xL can block np53 or mp53-mediated apoptosis [30–32]. When the expression of p53 is repressed, Bax and caspase-3 are downregulated in the heart tissue of CHD [33]. Interestingly, interaction also exists between the extrinsic and intrinsic pathways, evidenced by that Fas-mediated apoptosis can lead to mitochondrial damage through the caspase-8 cleavage of Bid [34].

2.2. The extrinsic pathway-induced apoptosis The extrinsic pathway-induced apoptosis is triggered by transmembrane death receptors which are members of tumor necrosis factor (TNF) receptor family and contain “death domain”. Several typical ligands and corresponding death receptors involving apoptosis-stimulating fragment ligand (FasL)/FasR, TNF-α/TNFR1, TNF-related apoptosis-inducing ligand (TRAIL)/DR4 and TRAIL/DR5 can help transmit death signals from cell surface to intracellular pathways through the 28

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2.4. The ER stress pathway-induced apoptosis

3.1. The morphology of autophagy

ER stress is a relatively new reported pathway in the regulation of apoptosis. It commonly results from some physiological or pathological insults including protein folding, intracellular Ca2+ stores, oxidative stress, hypoxia, ischemia and disorders of lipid metabolism [35,36]. Although ER stress is critical for cell survival [35], it also leads to apoptosis under chronic or prolonged stimuli [37]. It is sensed by an ER-specific UPR (unfolded protein response) which can be activated by three ER integral membrane proteins namely IRE1 (inositol-requiring protein-1), PERK (protein kinase RNA [PKR]-like ER kinase) and ATF6 (activating transcription factor-6) [38]. Specifically, prolonged IRE1 interplays with adaptor protein TRAF2 (tumor necrosis factor receptor (TNFR)-associated factor-2) and then initiates JNK (c-Jun N-terminal protein kinase) which has been demonstrated to involve in cell death [39,40]. It's therefore assumed that JNK is related to IRE1-mediated apoptosis. The possible mechanism may attribute to JNK-Bad signaling which involves in ER stress [41]. Notably, a previous study has revealed that mammalian IRE1α could bind Bak and Bax, thus leading to IRE1α activation [42]. Besides, procaspase-12 has been proved to interact with IRE1-TRAF2 complex, resulting in caspase-12 activation [43]. In addition, prolonged IRE1 may contribute to apoptosis by means of activating RIDD (regulated Ire1-dependent decay) pathway [44,45]; however, the specific mechanism underlying this pathway is unclear. Interestingly, IRE1α also splices and activates XBP1 (X-box binding protein 1) mRNA [46] which involves in cell survival. As a result, it's seen that IRE1α acts as a crucial protein and may be a shift of apoptosis and survival in response to ER stress. Regarding PERK, it promotes phosphorylation of the translation initiation factor eIF2α and induces translation of ATF4 which participates in proapoptotic process [36,38]. Under prolonged or extreme ER stress, ATF4 induces the expression of CHOP (C/EBP-homologous protein) [36]. Sustained evidences have showed that CHOP can suppress anti-apoptosis protein Bcl-2 [47] and increase pro-apoptotic proteins of Bim, Puma and Bax [48–51]. Furthermore, under oxidative stress circumstance, CHOP activates ERO1α (ER oxidase 1α) [52] and induces calcium-dependent apoptosis through CHOP-ERO1α-IP3R1‑calciumCaMKII pathway [53], followed by JNK activation and induction of Nox2 and ROS [54,55]. ROS can in turn activate PKR and thereby amplifies CHOP expression as a positive feedback [55]. Moreover, CaMKIIγ-induced apoptosis is related to JNK-Cyt c and JNK-Fas singlings as well [54]. Besides, caspase-12 and Bid are reported to involve in CHOP-ERO1α-IP3R‑calcium-calpain pathway during ER stress [56,57]. Of note, CHOP- and IRE1α-induced apoptosis could be avoided by a phenomenon called pre-conditioning, in which low-level ER stress could partially suppresse UPR before a robust UPR activator [58]. From the above results, it could be seen that positive relationships between ER stress-mediated and mitochondria-mediated apoptosis are established based on pro-apoptotic BCL2 proteins, resulting in the amplified apoptotic effect. In addition, ATF6 can activate XBP1 mRNA and exerts prosurvival effect [46]. Correspondingly, a study further indicates that inhibition of ATF6 can accelerate apoptosis as well [59]. However, the specific mechanism of ATF6-involved apoptosis is yet revealed.

Autophagy can be activated by a number of stimuli including nutrient starvation, glucose deprivation, caloric restriction, oxidative stress, and brief episodes of ischemia and reperfusion [61]. The autophagy process begins with formation of phagophore which is an isolation membrane and surrounds the damaged cytoplasmic materials and organelles. Then, phagophore elongates and fuses to form the mature double-membrane autophagosome with the help of several protein complexes involving Atg5 complex, class III phosphatidylinositol 3-kinase (PI3K)/Vps34 complex and microtubule-associated protein 1 light chain 3 (LC3, the main mammalian homolog of Atg8)-II. Eventually, the outer membrane of autophagosome fuses with a lysosome to produce an autophagolysosome, where the misfolded proteins and damaged organelles are degraded and removed by lysosomal hydrolases. As a result of autophagy process, nutrients of amino acids, fatty acids and simple sugars are released into the cytosol, which realizes the recycling of cytoplasmic components for protein synthesis and ATP production [62,63]. During the above process, more than 30 autophagy-related genes (Atgs) have been involved, especially in the formation of autophagosome [64]. Particularly, Atg5 complex is comprised of Atg5, Atg12 and Atg16L with correlation to Atg7 and Atg10. Two copies of Atg12-Atg5Atg16L dimerize to incorporate on the isolation membrane, which is essential for the recruitment of LC3-II [61]. With the assistence of Atg4, Atg7 and Atg3, LC3 is cleaved and LC3-I lipidates with phosphatidylethanolamine successively, thus resulting in the generation of LC3-II [65,66]. Of note, before or after the process of membrane fusion, Atg5 complex is dissociated but LC3-II remains incorporated on the autophagosomal membrane, which makes LC3-II a critical marker for the detection and monitor of autophagy [67,68]. In addition, class III PI3K complex contains class III PI3K, Beclin 1 (the mammalian homolog of Atg6), Atg14 and Vps15 [69–71]. The complex takes part in the formation of isolation membrane and recruitment of Atg proteins to the autophagosomal membrane [70]. More importantly, it also promotes the conjugation of Atg5-Atg12 [66]. As a result, the formation of autophagolysosome is a complex process and regulated by multiple factors (shown as Fig. 3). 3.2. mTORC1-mediated autophagy pathway mTORC1 is a sensor of cellular nutrient status [72,73] and usually activated by nutrient-rich conditions; in contrast, nutrient starvation suppresses mTORC1 [74]. Activated mTORC1 directly phosphorylates the Ser757 site of ULK1 (Unc51-like kinase 1, the mammalian homolog of Atg1) complex which contains ULK1, Atg13 and FIP200 [75,76], thus preventing the association of ULK1 with AMPK and possessing inhibitory effect on autophagy [76,77]. Besides, mTORC1 also promotes phosphorylation of Atg13 and then disrupts the ULK1 complex [78]. Of note, mTORC1 is directly activated by small Ras-like GTPase Rheb which is negatively regulated by the tuberous sclerosis complex 2 (TSC2) [79]. Through targeting TSC2, class I PI3K/Akt and AMPK can oppositely regulate mTORC1, thus exerting effects of inhibition and promotion of autophagy respectively [80–82]. 3.3. AMPK-mediated autophagy pathway

3. Molecular machinery of autophagy AMPK can sense energy status to maintain cellular energy homeostasis [83]. Under glucose deprivation, ischemia and oxidative stress, AMPK is phosphorylated and activated through the upstream serine/ threonine kinase LKB1 [84] when AMP/ATP ratio is upregulated [85,86]. Besides, AMPK can be also phosphorylated by the upstream kinase CaMKKβ in a Ca2 + −dependent manner [87]. Activated AMPK promotes autophagy through direct phosphorylation of ULK1 at Ser317 and Ser777 [76] or phosphorylation of Beclin1 at Ser91/Ser94 [88]. Moreover, it inhibits mTORC1 through the phosphorylation of TSC2

Autophagy is commonly categorized into three forms: macroautophagy, microautophagy and chaperone-mediated autophagy, of which macroautophagy is most well-characterized and studied [60]. Therefore, we predominantly discussed macroautophagy that is referred to as autophagy in this review. The molecular machinery of autophagy mainly consists of four pathways mediated by mTORC1 (mammalian target of rapamycin complex 1), AMPK (AMP-activated protein kinase), ER stress and p53 respectively (shown as Fig. 2). 29

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Fig. 2. The molecular machinery of autophagy in CHD. “→” represents promotion; “⊥” represents inhibition. “+P” stands for phosphorylation.

restriction [91]; however, another one illustrates that chronic calorie restriction and exercise initiate LC3-II protein rather than AMPK [92]. Therefore, as a frequently reported autophagic regulator, AMPK seems to exert distinct effects according to different stimuli which thereby deserve careful scrutiny. From the above mTORC1- and AMPK-mediated autophagy pathways, it can be seen that mTORC1 acts as a critical inhibitor of autophagy; while AMPK can be an autophagy activator. Complicated crosstalk exists between the two pathways involving common convergence of ULK1 and direct suppression of AMPK to mTORC1.

and mTORC1-Raptor complex [81,89]. Conversely, dominant negative AMPK can suppress glucose deprivation-induced autophagy in cardiac myocytes [90]. However, another research reports inconsistent result showing AMPK could inhibit cardiomyocyte autophagy under nutrientrich conditions [86]. When activated by acadesine (5-aminoimidazole4-carboxamide-1-β-D-ribofuranoside or AICAR), AMPK suppresses autophagy; whereas inhibition of AMPK enhances autophagy [86]. Interestingly, there are controversial results about the role of AMPK in calorie restriction-induced autophagy. A study supports that AMPK participates in the cardioprotective effects of short-term caloric

Fig. 3. The morphological process of autophagy. “→” represents promotion; “⊥” represents inhibition. 30

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establish the bridge of their interplay. Currently, the complex interplay becomes the increasing subject of intensive investigations [108–110]. It's reported that Beclin 1-Bcl-2/Bcl-xL complex [8,111], AMPK [112], mTOR, TRAIL, TNF-α, ER stress and np53 pathways [103,113,114] all participate in the positive or negative correlation between apoptosis and autophagy.

3.4. ER stress-mediated autophagy pathway Autophagy can be activated via IRE1/JNK/Hog1 pathway and ATF4-related signal during ER stress [93,94]. The potential mechanism may be that Hog1 stabilizes Atg8 (LC3) and thus induces autophagy [95]. Moreover, ER stress inhibitor or IRE1 knockdown triggers reduction of autophagy and decreased cell death in cardiomyocytes [93]. Besides, ATF4 is demonstrated to involve in the activation of both apoptosis and autophagy [36,94]. Regrettably, the mechanism underlying ATF4-mediated autophagy and its interaction with ATF4-mediated apoptosis are still unclear. In addition, under oxidative stress condition, H2O2-induced autophagy is dependent on increased ROS production which promotes Beclin 1 expression [96]. Besides, H2O2 also stimulates autophagy through oxidizing a cysteine residue of HsAtg4 and inhibiting its cysteine protease activity [97]. There is a positive feedback between oxidative stress and autophagy, which ultimately amplifies the autophagic cell death [98]. Of note, in response to growth factor deprivation, GSK3 (glycogen synthase kinase-3) activates and phosphorylates TIP60, resulting in acetylated ULK1 and activated autophagy [99].

4.1. Beclin 1-Bcl-2/Bcl-xL complex-mediated interplay As is known that Bcl-2 family proteins are important regulators in apoptosis; their significance in autophagy is also revealed by increasing studies. Bcl-2 and Bcl-xL are anti-apoptotic proteins and can bind to Beclin 1 which is enriched in mitochondria and ER and has a Bcl-2 homology 3 (BH3) domain [111]. After the interaction of Beclin 1 with Bcl-2 or Bcl-xL, Beclin1 is sequestrated away from Vps34/class III PI3K complex and autophagy is inhibited [8,115]; whereas Bcl-2 still remains anti-apoptotic potential [116]. The above inhibition of autophagy induced by Bcl-2 locates at ER instead of mitochondria [8]. Notably, the inhibitory effect is reversible when Beclin 1 is dissociated from the Beclin 1-Bcl-2/Bcl-xL complex and replaced with BH3-only proteins like Bad or BNIP3 [117,118]. Knockdown/mutations of BH3 domain within Beclin1 or BH3 receptor domain within Bcl-2/Bcl-xL can both disrupt the Beclin 1-Bcl-2/Bcl-xL complex, thus inducing autophagy and preventing apoptosis [10,108]. Similarly, phosphorylated Bcl2 by JNK1 also impedes the Beclin1-Bcl-2 complex and then promotes autophagy and inhibites apoptosis [112,119]. Further, AMPK can dissociate the complex of Bcl-2-Beclin1 and promote the formation of Beclin1-PI3K complex to enhance cardiac autophagy and protect cardiomyocyte against apoptosis in diabetes [112]. Moreover, AMPK phosphorylates and stabilizes p27 which prevents apoptosis but stimulates autophagy to protect cell from glucose starvation [120]. From the above results, it could be seen that Beclin 1-Bcl-2/Bcl-xL complex contributes to the positive relationship between autophagy and apoptosis; while a negative correlation can be estabilised through disturbing the complex (shown as Fig. 4a). It implies that Beclin 1-Bcl-2/Bcl-xL complex plays a crucial role for switching the relationship between the two responses, which may be helpful for CHD therapy in the future. In addition, Beclin 1 also exerts anti-apoptotic effect and depletion of Beclin 1 triggers caspase-dependent cell death in Caenorhabditis elegans [121]. Furthermore, pharmacological inhibitors or siRNAs targeting Beclin 1 or Atg7 markedly increase apoptotic cell death as well [122,123]. Therefore, Beclin 1 alone can build the negative relationship of autophagy and apoptosis. Although the specific mechanism underlying this phenomenon is unrevealed, it's likely that the apoptosis inhibition caused by Beclin 1 may attribute to its autophagy activation.

3.5. p53-mediated autophagy pathway p53 is a key regulator for sensing genotoxic and often acitivated by cellular stresses including hypoxia, growth factor deprivation and DNA damage [100]. Different from the pro-apoptotic function of np53 and mp53 [101], p53 has dual effects on autophagy, depending on its location at nuclear or cytoplasm (np53 or cp53) (shown as Fig. 2). Np53 promotes the activation of autophagy, leading to autophagic cell death; however, cp53 inhibits autophagy, accompanied by increased cell death as well [102]. As an important transcription factor, np53 enhances autophagy via activating the lysosomal protein DRAM (damage-regulated autophagy modulator) and increasing LC3 under stress condition [103]. Similay, in response to DNA damage, np53 activation also increases autophagy, which is influenced by np53 transcriptional activity [104]. Besides, another research indicates that np53 suppresses mTOR activity through initating AMPK and TSC1/TSC2 complex, resulting in activated autophagy [100]. Notably, it's differently reported that np53induced autophagy enhancement is transient; whereas prolonged activation of np53 leads to autophagy inhibition by np53-FBXL20-Vps34 pathway [105]. This result refers that the regulation of np53 on autophagy would vary according to the stimulation time, which deserves more supportive studies and evidences. However, regarding cp53, it's demonstrated to repress the activated autophagy in p53 (−/−) cells; moreover, the inhibition of cp53 accelerates autophagy in enucleated cells [106]. Further evidences indicate that no matter it is in human, mouse or nematode cells, the deletion, depletion or inhibition of cp53 all can enhance autophagy, resulting in the improvement of cell survival under circumstances of hypoxia and nutrition deprivation [106]. The potential mechanism may be regulation of AMPK and mTOR-mediated autophagy pathway, evidenced by the results that in p53 (−/−) cells, AMPK, TSC2 and acetyl CoA carboxylase (ACCα) are phosphorylated and activated; whereas mTOR activity is inhibited [106]. To explain this negative correlation between cp53 and autophagy, the study further points out that autophagy activation is used to resist the stress damage caused by cp53-deficiency [106]. As a result, from the above complicated results, it can be seen that both np53 and cp53 are cell death promotors whose nuclearcytoplasmic shuttling is regulated by some nuclear transport signals [107]. Differently, autophagy participates in the np53-mediated death; whereas death process caused by cp53 may be inhibited by autophagy.

4.2. mTOR pathway-mediated interplay mTOR can induce the interplay beteween apoptosis and autophagy as well. It's indicated that ablation of Raptor, the positive regulator of mTOR, could activate caspase-3 and lead to abnormal mitochondria, thus promoting both apoptosis and autophagy, accompanied by impaired adaptive hypertrophy and heart failure [124]. In addition, the mTOR pathway can be inhibited by BNIP3 which directly binds and inactivates Rheb, resulting in activation of autophagy and apoptosis and promotion of cell death under hypoxia comdition [125]. Therefore, mTOR induces positive relationship of apoptosis and autophagy, which may be mediated by the upstream activators of mTOR in a caspasedependent manner (shown as Fig. 4b). Moreover, the increased cell death following activated autophagy and apoptosis by mTOR suppression may contribute to the pathological process of CHD. Additionally, Atg proteins also involve in the interaction of apoptosis and autophagy. It's reported that Atg1 overexpression induces autophagy and apoptosis [126]. Autophagy can be activated by Atg7 and Beclin 1 as well as caspase-8 inhibition; moreover, application of caspase inhibitors in clinical inhibit apoptosis but promote autophagic

4. Interplay between apoptosis and autophagy Apoptosis and autophagy can be regulated by some common proteins and pathways. Further, they can interact with each other which 31

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Fig. 4. The interplay between apoptosis and autophagy. Figure (a) is Beclin 1-Bcl-2/Bcl-xL complex-mediated interplay; Figure (b) involves mTOR and TNF-αmediated interplay; Figure (c) is ER stress pathway-mediated interplay. “→” represents promotion; “⊥” represents inhibition. “+P” stands for phosphorylation.

complicated interplays are constructed by Atgs-caspases axis, Atg12Atg3-Bcl-2 and caspase-3-Beclin 1 (shown as Fig. 4b). According to different participating molecules, Atgs-caspases axis can induce distinct correlations; while Atg12-Atg3-Bcl-2 and caspase-3-Beclin 1 both trigger the negative relationship of apoptosis and autophagy. Furthermore, as it has been described above that Beclin 1 can promote autophagy and resist apoptosis, it's more exciting that when Beclin 1 interacts with caspase-3, the activation states of the two responses are reversed.

cell death [127]. Further, caspase-3 cleaves and triggers Atg4D which activates Atg8 (LC3); while Atg4D fragment enhances mitochondriamediated apoptosis [128]. In addition to the above Atgs-caspases axis, Atg12-Atg3 conjugation may also regulate mitochondria-associated apoptosis. It's reported that disrupting Atg12 conjugation to Atg3 can expand mitochondrial mass and suppress mitochondria-induced cell death, accompanied by inceased Bcl-2 protein rather than impaired Atg8 (LC3) lipidation and autophagosome formation [129]. Besides, Bax can inhibit autophagy evidenced by reduced LC3-II levels in a dosedependent manner [9]. Mechanically, the negative effect of Bax on autophagy appears to depend on caspase-3 activity which directly cleaves and inhibits Beclin 1 at 149D cleavage site [9]. In turn, the cleaved Beclin1 fragment further promotes apoptosis by increasing the release of Cyt c [130]. Interstingly, Bax-induced inhibition of autophagosome synthesis can be rescued by Bcl-xL [9]. As a result,

4.3. TRAIL and TNF-α pathway-mediated interplay TRAIL is a classic ligand that participates in the activation of extrinsic apoptotic pathway. A previous study has revealed that TRAIL promotes an autophagic program while activating caspase-mediated 32

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pathogenesis of CHD except for vascular smooth muscle cell (VSMC)induced atherosclerosis; whereas autophagy has dual and controversial function during ischemia, reperfusion and coronary atherosclerosis [6,90,133].

apoptosis during the process of lumen formation in MCF-10A human mammary epithelial cells [113]. Moreover, TRAIL also induces FADD and thus activates both apoptosis and autophagy; however, the above cell death pathway is selectively inhibited in immortal epithelial cells [114]. From the results, it's seen that a positive correlation between apoptosis and autophagy is supported by activated TRAIL; whereas the specific mechanism underlying this regulation is unclear. Furthermore, TNF-α stimulus can both repress and promote autophagy through activating NF-κB-mTOR pathway and ROS-dependent Beclin 1 overexpression respectively [96] (shown as Fig. 4b). The study further demonstrates that autophagy contributes to the apoptotic signaling under TNF-α stimulus; but caspase activation in turn inhibits LC3-II and autophagy [96]. Those above results mean that variable correlations can exist in autophagy and extrinsic apoptosis according to different pathways. Particularly, the interplay induced by TNF-α may be not equal, which therefore needs more verification in the future.

5.1. Myocardial infarction 5.1.1. Excessive apoptosis promotes myocardial ischemia damage Increased apoptosis is observed in the blood sample and heart tissue of patients with acute and subacute myocardial ischemia (AMI and SMI) [134,135]. A previous study has shown that apoptosis is the early and predominant form of cardiomyocyte death which preferres to locate at borders of the infarcted site [136]. Cleaved caspase-3 p17 peptide, the end effector caspase for apoptosis, is increased in STEMI (ST-segment elevation myocardial infarction) patients [137]. Besides, a close association between Bcl-2 rs17757541 C ≥ G polymorphism and high risk of CAD has been found in clinical practice [138]. Moreover, as the upstream regulator of Bax, p53 is accumulated in the heart tissue after myocardial infarction and increased in the monocytes of CAD patients, accompanied by up-regulated oxidative stress and apoptotic response [139]. In addition, TNF-α and TNFR1 are highly detected and would further predict infarct size of STEMI [134,140]. Particularly, TNFR1 correlates with cardiovascular prognosis closely in practice [141]. Although soluble Fas (sFas) receptor is markedly upregulated in AMI patients as well, the circulating levels of sFas and sFasL are not overall associated with infarct size and left ventricular (LV) dysfunction in STEMI patients after PCI [134,142]. Of note, opposite findings have been reported showing decreased TRAIL in patients with AMI [143] or CAD [144]. More importantly, TRAIL levels are inversely associated with the severity of CAD [144], acute coronary syndrome (ACS) [145] and the rate of cardiovascular events following AMI [143]. Those clinical results mostly demonstrate the significance of excessive apoptosis in myocardial ischemia, although apoptosis activation induced by different proteins and pathways may play distinct roles. Furthermore, some experimental researches receive consistent results. It's shown that downregulation of caspase-3 reduces infarct size, lowers apoptotic index of myocytes and ameliorates heart function in an AMI model [146]. Inhibition of Bax and promotion of Bcl-2 can suppress myocardial intrinsic apoptosis and further protect cardiac function from AMI [147]. TNF-α/TNFR1 complex contributes to extrinsic apoptosis in cardiomyocytes [148,149]. Similarly, ER stress pathway can lead to ischemia-induced cardiomyocyte apoptosis as well [150]. It's revealed that the dominant-negative form of XBP1 promotes cardiomyocyte apoptosis during hypoxia [151]; and inhibition of ATF6αaccelerates apoptosis, accompanied by increased LV diameter and reduced fractional shortening [59]. As a result, from the above clinical and experimental studies, it's shown that apoptotic signals of extrinsic pathway, intrinsic pathway and ER stress pathway all participate in the myocardial ischemia damage (shown as Fig. 1). Particularly, Bcl-2 and TNF-α/TNFR1 have more advantages as predictive factors.

4.4. ER stress pathway-mediated interplay ER is a key organelle in both apoptosis and autophagy. ER stress pathway is initially turned on in response to stimuli and insults, aiming at restoring the pathological tissue. Consecutively, under prolonged stresses, the UPR triggers apoptosis and autophagy as the final weapon to cope with the problem. Mechanically, IRE1-JNK-Hog1 and CHOP‑calcium-calpain signalings act as the common pathways involved in the process of apoptosis and autophagy [41,56,57,95,131]. A research demonstrates that activation of autophagy attenuates ER stress and apoptosis [14]. In addition, Atg5 can be cleaved by calpain during apoptosis; and apoptosis is at the same time facilitated based on interaction of cleaved Atg5 and Bcl-2 [131]. Controversially, another study indicates that ER stress can lead to cardiomyoblast autophagy and apoptosis through caspase-2/12 and IRE1α-JNK-Hog1-np53-Puma pathway under oxidative stress [93]. Therefore, ER stress builds another bridge for the interplay between apoptosis and autophagy. It's interesting that IRE1-JNK-Hog1 pathway-induced interplay is positive; whereas CHOP‑calcium-calpain pathway-regulated one is negative (shown as Fig. 4c). Notably, as it's discussed above that ATF4 is the upstream promotor of CHOP-induced apoptosis and participates in the activation of autophagy as well, there may exist ATF4-mediated positive interplay which thereby deserves further clarification. 4.5. np53 pathway-mediated interplay Np53 is a well studied promotor of apoptosis, which also participates in the regulation of autophagy. Studies have shown that np53 pathway builds another positive relationship between apoptosis and autophagy [103,104]. It's illustrated that np53-triggered autophagy can contribute to np53-dependent apoptosis in response to DNA damage [104]. The underlying mechanism may attribute to the activation of DRAM induced by np53, accompanied by increased autophagy and apoptosis, and promoted cell death [103]. Interestingly, DRAM is responsible for apoptosis activation by increasing autophagy, rather than direct effect of itself, which is evidenced by the experiment that Atg5 knockdown reduces both autophagy and apoptotic response [103]. Regrettably, in this study the specific mechanism how autophagy possesses pro-apoptotic effect is unrevealed. However, from the above results, the interplay between apoptosis and autophagy has been established and Atg5 may be one predicted target of np53-DRAM pathway (shown as Fig. 4c).

5.1.2. Activated autophagy protects myocardial ischemia from damage Under myocardial ischemia condition, cardiomyocytes lack sufficient glucose, amino acid and energy, which results in lowered ATP and induces activation of autophagy [152,153]. A study demonstrates that chronic ischemia stimulates autophagy in surviving cardiomyocytes but not in apoptotic ones [154]. Activated autophagy can in turn protect cardiomyocytes from AMI [155]. Mechanically, this ischemia-induced autophagic response is initiated by activation of AMPK and inhibition of mTORC1 signaling [153]. In contrast, in the presence of ample nutrient supply like high-fat diet, cardiac autophagosome maturation is disrupted and the cardioprotective effect is accordingly attenuated [156]. The potential mechanism may be activation of Akt signaling pathway, which suppresses autophagy through inhibiting TSC1/2 complex to activate mTORC1 [156,82] (shown as Fig. 2). Notably, ischemia induces the activation of ATF6; whereas

5. Role of apoptosis and autophagy in CHD Apoptosis and autophagy play significant roles in the occurrence, development and prognosis of CHD. It's reported that both apoptosis and autophagy are enhanced in patients with coronary artery disease (CAD) [132]. Excessive apoptosis usually acts as a promoter in the 33

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mediated pathways respectively [90,172]. It's possible that Beclin 1induced I/R injury may be amplified by AMPK deprivation; and activation of AMPK could be a treatment choice to reverse I/R injury.

reperfusion inhibits this protein. This phenomenon suggests that ATF6 involves in the induction of ER stress during ischemia, which may have a preconditioning effect of promoting cell survival during reperfusion [157]. The possible reason underlying the protection may attribute to autophagy which is associated with ischemic preconditioning (IPC) in some animal models. For example, increased LC3 and Beclin 1 are detected after IPC [158,159]; and induction of autophagy is required for the cardioprotective effects induced by IPC [160]. As a result, autophagy may be the underlying mechanism of IPC-induced protection, especially in the late phase of IPC [159]. The above researches illustrate that autophagy can protect myocardial ischemia from damage; regrettably, sufficient clinical investigations are still lacked to verify its efficacy and stability in practice.

5.3. Post-infarction cardiac remodeling 5.3.1. Enhanced apoptosis accelerates post-infarction cardiac remodeling Cardiac remodeling is commonly documented by LV remodeling which has characteristic of increased LV volumes and LV dysfunction. A clinical study has indicated that high level of myocardial apoptosis promotes LV remodeling and early symptomatic heart failure after infarction [175]. Moreover, apoptosis correlates with progressive parameters involving thickened posterior wall and myocardial fibrosis, accompanied by increased Bax in the infarction site of human heart tissues [176]. The potential mechanism may be not related to extrinsic apoptotic pathway, because there are little correlations between sTNFR1, sTNFR2, sFas and sFasL with measurements of remodeling in STEMI patients after PCI [134]. A further experimental reseach reveals that myocardial infarction-induced cardiomyocytes apoptosis attributes to CHIP-p53 pathway; when p53 is repressed, myocardial apoptosis and ventricular remodeling can be ameliorated [177]. As a result, from the above studies, it could be seen that apoptosis accelerates post-infarction cardiac remodeling; however, the underlying mechanism needs more sufficient clarification, especially for the intrinsic apoptotic pathway.

5.2. I/R injury 5.2.1. Increased apoptosis promotes I/R injury The process of I/R can lead to lethal levels of ROS, cellular injury and cardiovascular dysfunction, which may attribute to cardiomyocyte apoptosis. It's evidenced that upregulation of cardiac specific caspase-3 accelerates infarct size and increases risk of die after I/R injury [161]. Particularly, Fas pathway acts as a critical mediator of I/R-induced cardiomyocyte apoptosis [162]. Besides, TNF-α and TRAIL are also elevated during the onset of reperfusion in an I/R model [163]. Those above studies support the extrinsic apoptosis in I/R injury. While regarding intrinsic apoptosis, Bax overexpression exists in ischemic myocardial tissue and reduction of apoptosis is helpful for improvement of I/R injury [164]. Moreover, the cardiac specific overexpression of Bcl-2 can significantly relieve cardiomyocyte apoptosis and infarct size after I/R injury [165]. In addition, I/R injury is also triggered by ER stress-mediated apoptosis. Supportively, the PERK-ATF4-CHOP pathway-induced ER stress can transmit pro-apoptotic signaling [47,49]; moreover, inhibition of ER stress by inactivated Puma prevents I/R-induced cardiomyocyte death [36]. Other researchers report that AMPK negatively regulates ER stress and thus protects cardiomyocytes from damage [166]. This cardiomyocyte protection may depend on phosphorylation and inactivation of eEF2 (eukaryotic elongation factor 2) induced by AMPK during hypoxia [166] (shown as Fig. 1). Therefore, it's demonstrated that enchanced apoptosis promotes I/R injury; inhibition of apoptosis thereby becomes a promising method to improve the treatment effect of revascularization, which however deserves future verification in clinical practice.

5.3.2. Increased autophagy prevents post-infarction cardiac remodeling Autophagy is activated during post-infarction in surviving cardiomyocytes, as evidenced by the up-regulation of LC3-II, p62 and cathepsin D [178]. However, bafilomycin A1 (an autophagy inhibitor) significantly increases atrial natriuretic peptide and aggravates cardiac hypertrophy and remodeling, resulting in post-infarction cardiac dysfunction [178]. Therefore, it's indicated that autophagy can protect heart from post-infarction cardiac remodeling. Controversially, with respect to cardiac remodeling after hemodynamic stress, autophagy is a maladaptive response [179]. Overexpression of Beclin1 in the heart amplifies autophagy and accentuates cardiac pathological process in mice response to hemodynamic stress [179]. The potential mechanism may be related to BNIP3-induced autophagy which contributes to adverse ventricular remodeling [180]. However, another study reports inconsistent result indicating that autophagy maintains cardiomyocyte size, cardiac structure and function and thus protects heart from hemodynamic stress [181]. As a result, considering the cardiac remodeling caused by infarction or hemodynamic stress, autophagy may possesse distinct effects which need further verification.

5.2.2. Controversial effects of autophagy on I/R injury During reperfusion phase, the lack of ATP is no longer the main problem; instead, oxidative stress induces excessive production of ROS and becomes the main reason for autophagy activation [167,168]. Different from the protection of autophagy on myocardial infarction, autophagy exerts controversial effect on the pathological process of I/R injury [90]. It's indicated that autophagosome clearance is impaired during I/R injury, resulting in accelerated autophagy and cardiomyocyte death [169]. When Beclin1 heterozygous is knockout, I/R-induced autophagosome formation is significantly reduced, accompanied by lowered apoptosis and myocardial infarction [90]. Similarly, inhibition of autophagy by either 3-methyladenine or Beclin1 siRNA decreases I/ R-induced autophagy and promotes cell survival [170]. In contrast, another research shows that BNIP3-induced cell death can be reversed by the enhancement of Atg5-mediated autophagy, thus exerting resistence to I/R injury [171]. Further, inactivated AMPK is detected in reperfusion phase, which would lead to suppression of autophagy [90]. Other evidences indicate that AMPK deficiency can enhance myocardial I/R injury [172]; whereas, activated AMPK at reperfusion can protect against myocardial I/R injury and reduce infarct size [173,174]. Therefore, the controversial effects of autophagy on I/R injury could be observed through Beclin 1-mediated and AMPK-

5.4. Coronary atherosclerosis 5.4.1. Activated apoptosis contributes to coronary atherosclerosis except for VSMC-induced process Atherosclerosis is the basic pathogenesis of coronary vasculature for CHD. Abnormal apoptosis of vascular endothelial cell (VEC), macrophage or VSMC is the common character of atherosclerosis, contributing to the formation or instability of atherosclerotic plaques [51,182,183]. Evidences have shown that activated apoptosis could possess both detrimental and protective effects on coronary atherosclerosis, which depends on the types of vascular cells [51,184,185]. It's indicated that the oxidant hypochlorous acid-induced DNA damage, inflammation and atherosclerotic lesions are demonstrated to correlate with ER stress-meidated apoptosis. Specifically, 8-chloro-adenosine (8ClA), a chlorinated product of hypochlorous acid, can induce sustained ER stress and promote the release of calcium into the cytosol, thus resulting in enchanced apoptosis of human coronary artery endothelial cells (HCAECs) [184]. HCAECs apoptosis thereby accelerates endothelial damage which can finially initiate the development of coronary atherosclerosis. Besides, macrophage apoptosis is mediated by CHOP-Bax pathway during ER stress, which leads to the rupture of 34

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it still deserves more verification that whether the controversial effects are related to cell types. Mechanically, AMPK-induced autophagy is protective, while Beclin 1-mediated response participates in the deterioration of atherosclerotic plaques, which is similar to the dual effects of autophagy on I/R injury.

atherosclerotic plaques and thus increases the susceptibility to ACS [51]. In contrast, another research focuses on the relationship of apoptosis and atherosclerosis induced by inflammation, showing that IL-10 inhibits VSMC apoptosis through JAK2-STAT3 pathway during the formation of atherosclerosis [185]. The intrinsic apoptosis pathway may be involved, in that JAK2-STAT3 can increase Bcl-2 and suppress apoptosis [186] (shown as Fig. 1). As a result, excessive apoptosis of VECs and macrophages promote atherosclerosis; whereas VSMC-induced atherosclerosis attributes to its hyperproliferation and insufficient apoptosis. In addition to the above basic researches, a clinical study further reveals that sTRAIL-R2 and sTRAIL are related to human plaque cell apoptosis and plaque inflammation. High expressions of sTRAIL-R2 and sTRAIL proteins have been observed in symptomatic carotid plaques; moreover, patients with higher plasma level of sTRAIL-R2 are more likely to develop into future cardiovascular events [187]. Another investigation of 520 individuals shows that the Arg/Arg genotype of p53 is least expressed in patients with left main coronary artery disease, indicating that this gene polymorphism is high likely to negatively correlate with atherosclerosis process and cardiovascular prognosis [188]. Therefore, those above results show that abnormal apoptosis not only lays the foundation for formation and deterioration of coronary atherosclerosis, but can also early predict the risk of poor cardiovascular outcomes via detecting apoptosis-related markers.

6. Therapeutic implications of apoptosis and autophagy for CHD Since apoptosis and autophagy are essential for myocardial ischemia, I/R injury and post-ischemic cardic remodeling, regulation of the two adaptive responses represents appealing therapeutic implications for CHD. Currently, pharmacologic strategies targeting apoptosis and autophagy have been applied for CHD, which provide new promising therapeutic direction in the future. 6.1. The suppression of apoptosis Excessive apoptosis has been considered as a promotor for the pathological process of CHD. Suppression of apoptosis thereby becomes a promising method to treat this disease. It's convinced that several therapeutic drugs of CHD have been reported for their new function as apoptosis inhibitors. For example, olmesartan, a blocker of angiotensin II type 1 receptor, has been illustrated to suppress Fas-mediated apoptosis and improve post-infarction LV remodeling, accompanied by reduced levels of Fas, Bax, caspase-3 and c-Jun [192]. Simvastatin, a basic drug for regulating lipid metabolism, can decrease cardiomyocytes apoptosis and improve cardiac function after myocardial infarction, evidenced by downregualted Bax and caspase-3 and upregulated Bcl-2 [147]. Notably, angiotensin-converting enzyme inhibitors and βadrenergic receptor blockers can also reduce myocardial apoptosis and further improve clinical symptoms and prognosis in patients with postinfarction heart failure [193]. Additionally, other researches focus on pharmacologic compounds that may be specific inhibitors of apoptosis. It's indicated that salubrinal selectively inhibits the dephosphorylation of eIF2α and promotes cell survival at certain doses through resisting prolonged ER stress [194]. Moreover, EN460 (benzoic acid, 2-chloro-5[4,5-dihydro-5-oxo-4-[(5-phenyl-2-furanyl)methylene]-3-(trifluoromethyl)-1H-pyrazol-1-yl]) and QM295 (5(4H)-isoxazolone,4-[(4hydroxy-3-methoxyphenyl)methylene]-3-phenyl), two selective ERO1 inhibitors, can protect mouse embryonic fibroblast from lethal levels of ER stress and improve cell survival against tunicamycin [195]. Specifically, EN460 is more potent but limited by toxicity at the highest concentrations compared with QM295 [195]. Besides, a chemical chaperone, 4-phenyl butyric acid (PBA), has been used to relieve pathologic ER stress in atherosclerosis induced by lipotoxic signals, although the therapeutic mechanism linked to apoptosis is still uncertain [196]. Furthermore, 17-allylamino-17-demethoxy geldanamycin (17AAG) can repress p53 and inhibit myocardial apoptosis [177]. Interestingly, as NF-κB has been previously considered as an important apoptotic activator by targeting p53 [197] and negatively regulated by Bcl-2 [198], a study indicates that administration of M2b macrophages markedly attenuates early myocardial I/R injury through impeding NFκB signaling via increasing A20 (TNF-α induced protein 3, TNFAIP3) level [199]. However, although TNF-α is an important activator of extrinsic apoptosis, application of its antagonist, etanercept, has not received expected effect in AMI patients [200]. It indicates that the function of TNF-α in CHD is complicated and simple inhibition of all TNF-α may be not specific for cardiac patients. In contrast, psoriasis patients can benefit from the anti-TNF-α therapy, evidenced by lower risk of myocardial infarction compared to topical agents [201]. Therefore, it's identified that not all regulators involved in apoptosis can become treatment agents and those candidates illustrated in cells or animals should be further confirmed by clinical trials. Importantly, as some apoptotic regulators play roles in more than one pathway, there has been a speculation that treatment targeting pro-apoptotic Bcl-2 family

5.4.2. Accelerated autophagy exerts controversial roles in coronary atherosclerosis Autophagy involves in the process of coronary atherosclerosis as well, but its specific roles are dual and controversial. Some researches consider it as a protective factor for prevention of atherosclerosis. It's indicated that autophagy is inhibited in cardiovascular patients, accompanied by decreased LC3 and Atg5 genes [189]. Further experiments reveal that rapamycin (a mTOR inhibitor, also called sirolimus) treatment for patient-derived macrophages can downregulate ApoB expression and then decrease LDL, IL-6 and TNF-α levels, illustrating the protective role of autophagy in macrophages-induced lipoprotein metabolism disorder and vascular inflammation [189]. Besides, in human coronary artery VSMCs, autophagy involves in the improvement of lipid accumulation and atherosclerosis plaque formation induced by SCAP (Sterol regulatory element binding protein cleavage-activating protein, a key cholesterol promotor) knockdown under the circumstance of LDL stimuli. The potential mechanism may be the suppression of oxidative stress and promotion of AMPK phosphorylation in vivo and in vitro [133] (shown as Fig. 2). Similarly, C1q/tumor necrosis factorrelated protein 13 (CTRP13), a secreted adipokine related to glucose and lipid metabolism, also regulates atherosclerosis by targeting autophagy. It's demonstrated that CTRP13 can trigger autophagy-lysosome-induced degradation of differentiation 36 (CD36) protein cluster, and thus prevent coronary atherosclerotic plaques, evidenced by obvious reduction of macrophage content, lesion areas, oxidized-LDL uptake and foam cell migration in vivo and in vitro [190]. By contrast, inhibition of autophagy-lysosome increases CD36, and then promotes the formation and migration of foam cell, reversing the protective roles of CTRP13 in atherosclerosis [190]. However, other researches indicate opposite results showing that autophagy deteriorates coronary atherosclerosis [6,191]. TNF-α is demonstrated to upregulate the expression of Beclin 1 and LC-3 and thus promote autophagic death of VSMCs by increasing JNK [191], leading to the instability of atherosclerotic plaques (shown as Fig. 2). Moreover, when the autophagy of endothelial progenitor cell is inhibited, increased cell viability and reduced apoptosis level are observed for CAD. The potential mechanism attributes to activation of mTOR signaling pathway [6]. From the above results, it's shown that autophagy-mediated effects of anti-atherosclerosis and coronary protection mainly benefit from lipid regulation in macrophages; whereas enhanced autophagy of VECs can induce the progress of atherosclerosis. Therefore, 35

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importantly, the Beclin 1-Bcl-2/Bcl-xL complex can be dissociated by Bad, BNIP3 or AMPK, resulting in a negative correlation which activates autophagy but suppresses apoptosis [112,117,118]. Further, Beclin 1 can promote autophagy as well as reduce apoptotic cell death [122]; whereas caspase-3 activation induced by Bax cleaves Beclin 1 and then reverses the above effects [9]. Interestingly, ER stress-mediated apoptosis and autophagy may interact with each other in a controversial method. The interplay induced by IRE1-JNK-Hog1 pathway is positive; whereas CHOP‑calcium-calpain pathway promotes the negative relationship [93,131]. Of note, TNF-α-induced autophagy contributes to apoptotic signaling; nevertheless, caspase activation suppresses autophagy [96]. Therefore, it could be speculated that fixed relationship may not exist between apoptosis and autophagy in all contexts. Instead, their interplay could vary according to the kinds of activated pathways which may depend on the types of cells and diseases. Although previous reviews have reported the relationships between apoptosis and CHD [23,213] or autophagy and CHD [61,86], a systematic overview about the interplay of apoptosis and autophagy and their therapeutic implications for CHD still lacks. As a result, we performed the review with the aim of clarifying the interplay and treatment of the two responses to promote better understanding and management of CHD. From our above review, it could be seen that apoptosis and autophagy interact with each other through several different pathways and thereby participate in the pathological process of CHD (shown as Fig. 5). Excessive apoptosis of cardiomyocytes, VECs or macrophages contributes to myocardial ischemia, I/R injury, post-ischemic cardiac remodeling and coronary atherosclerosis; whereas proliferative VSMCs with decreased apoptosis is one reason for the progress of atherosclerosis [51,148,162,176,185]. In contrast, enhanced autophagy has dual effects on CHD. It protects myocardium against ischemia and post-ischemic cardiac remodeling [178,153]; but possesses either detrimental or preventive role in I/R injury and coronary atherosclerosis [90,171,189,191]. Those controversial effects may attribute to distinct pathways of autophagy activation during I/R and coronary atherosclerosis. Specifically, AMPK is activated and participates in the protective autophagic response induced by ischemia or atherosclerosis [133,153]; whereas AMPK deficiency exists in reperfusion and enhances I/R injury [90,172]. Comparatively, Beclin 1 is upregulated by reperfusion or atherosclerosis, which adversely promotes detrimental autophagosome formation [90] [191]. Of note, further studies are still needed to reveal whether the above controversial effects are related to cell types. Additionally, apoptosis- and autophagymediated regulation of CHD can be targeted by miRNAs respectively [214,215]. More interestingly, as Beclin 1-Bcl-2 complex contributes to the complicated interplay between apoptosis and autophagy, a study futher reveals that this bingding complex can be targeted by miR-34a5p, thus leading to regulation of both autophagy and apoptosis in HCAECs [216]. Therefore, apoptosis and autophagy possesse essential and diverse roles in CHD; and the complicated interplay between them may be controlled by upstream miRNAs. In addition, apart from the macroautophagy described above, mitophagy, a non-random and selective process of mitochondrial autophagy [217], also correlates with CHD [218]. It participates in IPC by recognizing an essential Parkin protein, aiming to selectively degrade the damaged mitochondria and exert cardioprotective function [219]. Further, cp53 can suppress Parkin-induced mitophagy and accelerate the dysfunction of cardiac mitochondria, thus disturbing the above protective effect [220]. Interestingly, those results are consistent with macroautophagy-mediated anti-ischemic effect of IPC and the cp53induced inhibition of macroautophagy [106,160], indicating possible relationship between mitophagy and macroautophagy in the context of CHD. However, current evidences are inadequate; more reseaches still need to clarify and verify whether macroautophagy and mitophagy are relational or not and to what extent they may interact with each other. Apoptosis and autophagy have significant therapeutic implications

members or JNK, and management of drug combination would be better choice [45]. 6.2. The regulation of autophagy As autophagy exerts dual roles in CHD, it would be advisable to keep the activity of autophagy balanced according to the context. A previous study has revealed that myocardial reperfusion therapy like percutaneous coronary intervention (PCI) can be obstructed by coronary microembolization (CME) which induces no-reflow or slow reflow and then reduces the efficacy [202]. The inhibitory mechanism may attribute to downregulation of miR-30e-3p and LC3-II, upregulation of p62 and cTnI level, leading to reduced autophagy and cardiac function [203]. The above results indicate that CME-induced efficacy attenuation may be related to downregulated autophagy which is targeted by miR-30e-3p. In constrast, by increasing cardiac autophagy, calorie restriction can improve myocardial ischemia tolerance and thus prevent obesity-related damages [91]. Therefore, it could be seen that regulation of autophagy may be a therapeutic method for CHD. Currently, two classical antimicrobial agents, sulfaphenazole (SUL) and chloramphenicol (CAP), have been reported to inhibit cytochrome P450 and protect myocardium from I/R injury [204,205]. Further evidences reveal that SUL-induced cardioprotection attributes to protein kinase C-dependent induction of autophagy, evidenced by the enhancement of cardiac function and reduction of infarct size [206]; moreover, CAP administration affords profound cardioprotection accompanied by elevated LC3 and Beclin 1 levels, and reduced infarct size [205]. In addition, other researches reveal the positive effect of metformin on diabetic cardiomyopathy through induction of cardiac autophagy [207]. As a result, those medicines could be preferable choices for CHD patients with infection or diabetes compared with other drugs. Notably, as mTOR plays critical role in the inactivation of autophagy, mTOR inhibitors such as rapamycin and everolimus (also called RAD) may be promising candidates. Although mTOR inhibitors are usually considered as immunosuppressants and mainly applied for transplantation medicine, their positive roles in CHD have been emerging. A randomized, double-blind and placebo-controlled trial demonstrates that rapamycin is effective to prevent restenosis after coronary angioplasty [208]. More experimental evidences support that rapamycin treatment mitigates post-infarction adverse remodeling, LV hypertrophy and cardiac dysfunction; however, the protective effect can be offset by bafilomycin A1 [178,209]. Besides, autophagic activity induced by rapamycin improves ER stress, apoptosis and atherosclerosis [14]. Regarding RAD, it increases autophagy and relieves adverse remodeling in the border zone of infarction; nevertheless, it does not decrease autophagosome clearance [210]. In addition, acadesine is a pharmacological activator of AMPK. A previous meta-analysis has shown that acadesine management before and during CABG surgery can release MI, decrease early cardiac death and adverse cardiovascular outcomes [211]. More importantly, acadesine is pharmacologically silent at normal circumstances, but becomes positive through net ATP catabolism, which helps to avoid potential side effects [212]. However, whether the above myocardial protection caused by AMPK is related to AMPK-mediated autophagy warrants further demonstration. 7. Discussion Apoptosis and autophagy can be both mediated by several pathways respectively, of which ER stress and p53-related pathways are shared. Owing to some protein interactions and common pathways, the complicated interplay between the two responses is established (shown as Fig. 5). Beclin 1-Bcl-2/Bcl-xL complex, mTOR, TRAIL and np53 build the positive correlation between apoptosis and autophagy. Specifically, Beclin 1-Bcl-2/Bcl-xL inhibits the two responses [8]; whereas mTOR inhibitor, TRAIL and np53 all promote them [104,113,124]. More 36

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Fig. 5. The overall mechanical pathways of apoptosis and autophagy in CHD. “→” represents promotion; “⊥” represents inhibition.

for CHD. Our above review has shown that several drugs involving RASS blocker, β receptor blocker, simvastatin, antimicrobial agents and metformin have been illustrated to exert regulatory function on apoptosis or autophagy. Furthermore, pharmacologic compounds that target the interplay of apoptosis and autophagy may possess more direct and applicable potential as therapeutic candidates. For example, studies have illustrated that mTOR inhibitors can promote autophagy and improve apoptosis to prevent atherosclerosis and coronary restenosis in vitro and in vivo [14,208]; moreover, AMPK activator is beneficial for I/R injury and CHD patients after CABG surgery [174,211]. Nevertheless, as mTOR- and AMPK-mediated signaling pathways participate in various physiological and pathological processes, inhibition of their activities may thus lead to other unexpected results. Pariticularly, mTOR inhibitor-related pneumonitis has aroused researchers' attention [221,222]. Comparatively, drugs targeting the dissociation of Beclin 1Bcl-2/Bcl-xL complex may be better choice, as this complex is an adjustable switch between apoptosis and autophagy, especially for the treatment of myocardial ischemia and post-ischemic cardiac remodeling where opposite effects are generated from apoptosis and autophagy. Regrettably, few compounds have been recently discovered to disturb the Beclin 1-Bcl-2/Bcl-xL complex both in experimental and clinical studies. As a result, in spite of current achievements, more indepth researches about apoptosis and autophagy in CHD are still deserved to improve the management of the disease.

[6]

[7] [8]

[9] [10]

[11] [12] [13] [14]

[15] [16]

[17] [18]

Disclosures

[19]

None.

[20]

Acknowledgements [21]

We are grateful to our lab members as well as to the department of cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences. This work was supported by the National Natural Science Foundation of China (No. 81673847).

[22]

[23]

Author contributions

[24]

Jie Wang designed the study. Yan Dong, Hengwen Chen, and Jialiang Gao conducted searches and extracted the data. Yongmei Liu, Jun Li and Yan Dong analyzed the data. Yan Dong wrote the manuscript.

[25]

[26] [27]

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