Is CD47 a potentially promising therapeutic target in cardiovascular diseases? — Role of CD47 in cardiovascular diseases

Journal Pre-proof –role of CD47 in cardiovascular diseases

Quanli Cheng, Junlian Gu, Binay Kumar Adhikari, Liguang Sun, Jian Sun PII:

S0024-3205(20)30173-9

DOI:

https://doi.org/10.1016/j.lfs.2020.117426

Reference:

LFS 117426

To appear in:

Life Sciences

Received date:

9 October 2019

Revised date:

3 February 2020

Accepted date:

9 February 2020

Please cite this article as: Q. Cheng, J. Gu, B.K. Adhikari, et al., –role of CD47 in cardiovascular diseases, Life Sciences(2020), https://doi.org/10.1016/j.lfs.2020.117426

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Journal Pre-proof Is CD47 a potentially promising therapeutic target in cardiovascular diseases？ --Role of CD47 in cardiovascular diseases Quanli Cheng MDa, Junlian Gu MD,PhDb, Binay Kumar Adhikari MDa, Liguang Sun PhDc*,Jian Sun MD,PhD d*

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Author information

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a The First Hospital and Center of Cardiovascular Diseases, Jilin University, Changchun, China.

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b The School of Nursing, Shandong University, Jinan ,China

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c The First Hospital and Institute of Immunology, Jilin University, Changchun, China. Electronic

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address: [email protected] number: +8613756466977. d The First Hospital and Center of Cardiovascular Diseases, Jilin University, Changchun, China.

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Electronic address: [email protected]. Telephone number: +8613844038776

Journal Pre-proof Abstract CD47 (cluster of differentiation 47) is a ubiquitously expressed transmembrane protein that belongs to the immunoglobulin superfamily. CD47 is both a receptor for the matricellular protein thrombospondin-1 (TSP-1) and a ligand for signal-regulatory protein alpha (SIRPα). Suppression of CD47 activity enhances angiogenesis and blood flow, restores phagocytosis by macrophages,

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improves ischemic tissue survival, attenuates ischemia reperfusion injury, and reverses atherosclerotic plaque formation. In conclusion, these observations suggest a pathogenic role of

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CD47 in the development of cardiovascular diseases (CVDs) and indicate that CD47 might be a

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potentially promising molecular target for treating CVDs. Herein, we highlight the role of CD47

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in the CVD pathogenesis and discuss the potential clinical application by targeting CD47 for

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treating CVDs.

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Keywords: CD47; therapeutic target; cardiovascular diseases

Journal Pre-proof Introduction Cardiovascular diseases (CVDs) are disorders of the heart and blood vessels, including coronary heart disease, cerebrovascular diseases and peripheral artery diseases. CVDs are the leading cause of death worldwide [1-4]. Currently, 17.7 million people per year die from CVDs, accounting for 31% of all global deaths (http://www.who.int/cardiovascular_diseases/world-

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heart-day-2017/en/). Thus, CVDs present a major public health and economic concern. Therefore, extensive efforts have been made to understand the etiology of CVDs and devise preventive and

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therapeutic measures to manage CVDs. Despite the rapid advances in the field, including new

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mechanisms underlying the pathogenesis of CVDs and novel treatment technologies, CVDs

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remains poorly understood.

CD47 (cluster of differentiation 47), also referred to as integrin associated protein (IAP) [5] and

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ovarian cancer antigen (OA3) [6], is a ubiquitously expressed transmembrane protein that

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belongs to the immunoglobulin superfamily. CD47 plays an important role in multiple fundamental cellular functions, including apoptosis, proliferation, adhesion, and migration [7-9].

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CD47 has been extensively studied in cancer [7, 10-12]. In addition, inhibiting CD47 with antibodies restored phagocytosis and prevented atherosclerosis [13], indicating a potential pathogenic role of CD47 in CVDs. Indeed, accumulating evidence has suggested that CD47 contributes to the development of human CVDs [13-17]. Here, we review previous studies that have implicated CD47 in the development of CVDs and provide support for CD47 as a potential therapeutic target for treating CVDs. 2. CD47 structure and functional partners

Journal Pre-proof CD47 is a 50-kD transmembrane protein [5] that consists of an extracellular N-terminal IgV domain, five transmembrane domains, and a short C-terminal intracellular tail [18, 19]. CD47 has four alternatively spliced isoforms, which differ only in the length of their cytoplasmic tails [20]. Functionally, CD47 serves both as a receptor for the matricellular protein thrombospondin1 (TSP-1), [21] and as a ligand for signal-regulatory protein alpha (SIRPα) [22] (Figure a).

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TSP1 is a large matricellular glycoprotein that contains an N-terminal heparin-binding domain, a

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procollagen domain, and a carboxy-terminal domain [23-25] (Figure a). TSP1 was first found in

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blood platelets upon thrombin activation in 1978 [23], and was later found to be produced and

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secreted by multiple cells, including fibroblasts [26], endothelial cells [27], and vascular smooth muscle cells (VSMCs) [28] on activation. Recent studies have shown that TSP1 mediates vessel

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wall pathophysiology in CVDs [16, 29, 30](Figure a).

SIRPα is also a transmembrane protein, and is particularly abundant in the myeloid-lineage

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hematopoietic cells, including macrophages and dendritic cells (DCs) [31-33]. SIRPα consists of

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three Ig-like domains in the extracellular region, a single V-set and two C1-set IgSF domains, a single transmembrane region, and four tyrosine residues for putative tyrosine phosphorylation in the cytoplasmic region [8, 34-36] . SIRPα acts as an important inhibitory receptor and can be activated by CD47. Since the CD47-SIRPα axis delivers inhibitory signals for phagocytosis it is also referred to as the “don‟t eat me” signaling pathway. This axis suppresses innate immune surveillance and elimination in multiple tumors [37-39]. However, a recent study has demonstrated that the CD47-SIRPα signaling pathway also plays a critical role in promoting atherosclerosis [13](Figure a).

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Figure a：CD47 structure and its major partnersand the role of CD47 in atherosclerosis and I/R injury

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During the development of atherosclerosis, TNFα act on TNFR1-induced up-regulation of CD47 and NFKB1 to combine with CD47 promoter, intensify CD47-SIRPα (“don‟t eat me”) signaling and interrupt phagocytosis of apoptotic bodies, while anti-CD47 antibody treatment reverses these effects. After myocardial ischemiareperfusion(I/R), CD47 expression is up-regulated in the dying myocytes, which suppresses phagocytosis of macrophages via CD47-SIRPα signaling and increases oxidative stress, decreases NO levels via TSP1-CD47 signaling. Inhibition of CD47 reduces cardiac inflammation and infarct size and improved cardiac contractile function.

3. General pathophysiological activity of CD47

Journal Pre-proof 3.1 CD47 inhibition increases blood flow, promotes angiogenesis, and improves ischemia reperfusion injury via the TSP1- CD47 signaling pathway Endothelium-derived nitric oxide (NO) is a powerful vasodilator [40]. CD47 activation by TSP1 limits endothelial-dependent arterial relaxation and decreases blood flow by inhibiting endothelial NO synthase (eNOS) activation through directly reducing NO release [16] ,and CD47 is indispensable for TSP1 mediated inhibition of NO-driven vascular cell responses to

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pathological stimuli [16, 41]. This functional axis limits eNOS activation and reduces NO

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production through suppressing cMyc to up-regulate endothelin-1/endothelin receptor (ET-

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1/ETA) to induce vasoconstriction [42], possibly via ET-1/ETA impairment of NO signaling in endothelial cells by targeting eNOS [43],or altering the constitutive interaction between CD47

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and caveolin-1 (cav-1), leading to „uncoupling‟ of eNOS ,which promotes the production of

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eNOS-derived superoxide [44]. In addition, activation of this TSP1-CD47 pathway increases

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reactive oxygen species (ROS) production via stimulation of NADPH oxidase 1 (Nox1), which interferes with NO bioavailability and action [45] and accelerates endothelial cell replicative

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senescence and associated cycle arrest [27], leading to arterial dysfunction(Figure b). Consistent

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with the above observations, the TSP1-CD47 axis was found to suppress accumulation of cGMP stimulated by NO-driven soluble guanylate cyclase (sGC) activators in endothelial cells [46], VSMCs [47] and platelets [47, 48], thereby decreasing the vascular response and inducing platelet aggregation. Furthermore, inhibition of CD47 was found to enhance the angiogenic response [14]. For example, CD47-deficient mice exhibit improved angiogenesis and vascular integrity compared to wildtype mice, which was mainly attributed to the loss of TSP1-CD47 signaling, vascular endothelial growth factor receptor (VEGFR) expression, and VEGF production [49]. Therefore, inhibiting CD47 can also protect against myocardial ischemia and

Journal Pre-proof reperfusion (I/R) injury, which may be a result of increased NO synthesis, elevated NO levels, decreased oxidative stress [17], enhanced angiogenesis [49] ,and/or rescue autophagic clearance[50] .Similar protection resulting from CD47 inhibition was also observed in other organs, such as kidney [51, 52] and liver [15]. Overall, suppression of TSP1-CD47 signaling can

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enhance blood flow and angiogenesis, and therefore improve ischemic tissue survival.

Figure b:How TSP1-CD47 pathway affects NO signaling TSP-1 functions as a ligand by binding and activating CD47. The signal limits eNOS activation by „uncoupling‟ with cav-1 or suppressing cMyc to up-regulate ET-1/ETA, and at last decreases NO levels. Simultaneously, activation of the TSP1-CD47 axis impairs NO signaling by increasing ROS production via

Journal Pre-proof stimulation of Nox1. Together, these direct and indirect processes promote vasoconstriction and decrease blood flow.

3.2 CD47 inhibition restores macrophage mediated phagocytosis via suppression of CD47SIRPα signaling When CD47 interacts with its receptor, SIRPα, it initiates a signaling cascade whereby src homology-2 domain containing protein tyrosine phosphatases SHP-1 and SHP-2 are recruited,

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which in turn conveys inhibitory signals for phagocytosis [8, 35]. Therefore, the CD47-SIRPα

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signal is also called the “don‟t eat me ”signal. Correspondingly, loss of CD47 leads to

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homeostatic phagocytosis of aged or damaged cells [53, 54]. Conversely, high CD47 expression on the cell surface inhibits macrophages, while the anti-CD47 antibody reverses the negative

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effect of CD47 on tumor cells [55], leukemia cells [56], and platelets in immune

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thrombocytopenia [57]. Similar findings have been observed in atherosclerosis. In physiological conditions, diseased vascular cells and apoptotic debris are phagocytosed by macrophages in a

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timely manner. overexpression of CD47 activates SIRPα and inhibits phagocytosis, leading to

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the pathological accumulation of diseased vascular cells and apoptotic cells. However,

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administration of anti-CD47 antibodies restores phagocytosis, normalizes the clearance of diseased vascular tissue, and ameliorates atherosclerosis [13]. In the past few years, studies have also shown that fibroblasts are surrounded by macrophages and CD47-inhibition attenuates fibrosis by restoring macrophage mediated phagocytosis induced by CD47-SIRPα signaling [58](Figure a ). 3.3 CD47 plays a critical role in inflammatory response

CD47 is characterized as an inflammatory mediator. On the one hand, high expression of CD47 promotes inflammatory response. Recent studies show that CD47 expression is significantly up-

Journal Pre-proof regulated after MI both in the ischemic area of human hearts ranged from 6h to seveal days and mice hearts after myocardial I/R( occluded the left coronary artery for 45min and reopened it for reperfusion ),which leads to the impairment of necrotic myocyte clearance timely, resulting in aggravation of inflammatory response, while CD47 blockade reverse the effect[17, 59]. CD47 deficiency or inhibition dampens the production of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) [60-62], resulting in protection in response to inflammatory stimuli [63]. In

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addition, other studies have shown that CD47 can act as a T-cell recruiter that promotes

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inflammatory cell adhesion and transendothelial migration independent of known partners,

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SIRPα and TSP1 [64-67].On the other hand, the authors found that CD47 is gradually up-

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regulated during the development of atherosclerosis ,and TNFα acting on TNFR1 induced upregulation of CD47. Furthermore, the classic pro-inflammatory factor NFKB1 (P50) was

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positively correlated with the expression of CD47 in human coronary and carotid plaques. The

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chromatin immunoprecipitation test confirmed that NFKB1 combined with CD47 promoter in vitro. In human smooth muscle cell culture, after adding TNFα, CD47 is up-regulated within 24

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hours, while after adding TNFα and NFKB1, CD47 up-regulation only needs 90 minutes, which

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can be reversed by adding anti-CD47 antibody, and this effect is most obvious in the case of dyslipidemia and atherosclerosis[13].Similarly, the researchers found that activation of the TNFα-nuclear factor kappa-B1 (NFKB1) pathway directly up-regulates CD47 in cancer [69]. These findings collectively point to the existence of a vicious circle between CD47and inflammatory response (Figure c).

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Figure c: Role of CD47 in inflammatory response

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CD47 promotes inflammatory response through inhibiting phagocytosis (intensify “don„t eat me ” signal),

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promoting TNFα/IL-1β production and T-cell recruitment. In turn, the pro-inflammatory factor TNFα and NFκB1 (P50) directly up-regulates CD47. These findings collectively point to the existence of a vicious circle

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between CD47 and inflammatory response .

CD47 indicates inflammation associated with specific cell types. In a recent study, Ganesh et.al [70] analyze leukocytes to describe which cell subtype expresses CD47 in the infarct left ventricle and spleen by flow cytometry, and found CD47 expresses on the neutrophils (CD45 + / CD11b + / F4 / 80 − / ly6g +).After sub-acute treatment of carprofen(CAP) ,CD47 expression increases on neutrophils (Ly6G+) in the infarcted left ventricle and spleen, and its receptor SIRP� also increases on M�s , showing a CAP intensified “don‟t eat me” signal, which deffer

Journal Pre-proof the phagocytosis of certain cells after cardiac ischemic injury that promotes non-resolving inflammation[70].Additionally,as we discussed above, CD47 up-regulation is related to the inflammation of atherosclerotic plaque, but the researchers confirm that CD47 is specifically expressed on lesional cells in atherosclerotic plaque, including smooth muscle cells (αSMA) and

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macrophages(CD68) and cells undergoing programmed cell death (Casp3) [13].

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However, CD47 can also function as a self-controlled negative regulator to ameliorate inflammatory responses, as evidenced by the findings that CD47 deficient T cells promote Th1

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differentiation and exacerbate the type 1 immune hypersensitivity response [71]. Similarly,

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Studies show that CD47 can be added to biomaterials to mitigate the inflammatory response and

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enhance biocompatibility via CD47-SIRPα signaling. This signaling cascade diminishes inflammatory cells, platelet adhesion , and activation. Interestingly, these findings strongly

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suggest that the role of CD47-SIRPα signaling to influence the immune responses beyond the

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canonical role as an inhibitor of phagocytosis .These may represent an immense opportunity for the application of CD47-modified biomaterials in developing kinds of medical devices and

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therapeutic drug delivery systems. [72-75].Hence, CD47‟s ability to either inhibit or stimulate an inflammatory response is context-dependent.

4. CD47 and CVDs CVDs are the leading cause of death worldwide [1-4], resulting in economic burdens and public health issues. Identifying novel mechanisms underlying CVDs development may lead to more efficient treatment of CVDs. Accumulating evidence suggests that CD47 may be potentially new therapeutic target in CVDs treatment [13-17, 76] .

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Journal Pre-proof 4.1 CD47 inhibition attenuates coronary artery disease Atherosclerosis is the basis of most CVDs, including myocardial infarction and stroke. However, the mechanisms leading to atherosclerosis remain incompletely understood. In a recent study, Kojima et al. [13]found the expression of CD47 in human carotid and coronary arteries is increased, and appears to concentrate in necrotic core of the plaques. Moreover, the expression of CD47 in atherosclerotic plaque of patients with transient ischemic attack or stroke was higher

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than that of patients without symptoms. Furthermore, CD47 is gradually up-regulated during the

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development of atherosclerosis, which may well explain why the phagocytosis of atherosclerotic

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plaque is impaired. Based on this, the authors treated a cohort of atherosclerotic animals

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(ApoE−/− mice implanted with Angiotensin II-infusing minipumps ) with anti-CD47 antibody. As expected, anti-CD47 antibody treatment can significantly reduce the atherosclerosis of the

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aortic sinus and aorta, including reducing necrotic core and apoptotic bodies. Several additional

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experiments have further confirmed the result. In the aspect of mechanistic studies, CD47, combining with SIRPα, leads to the phosphorylation of SHP1 and interrupts phagocytosis. Anti-

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CD47 antibody treatment is related to the inhibition of phosphorylation of SHP1, causing

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interruption of the "don't eat me" axis and promoting phagocytosis. In addition,TSP1, the ligand of CD47, can promote nitric oxide (NO) production and improve endothelial function, while CD47 can participate in atherosclerosis independently of TSP1. However, possibly due to the large molecular weight of anti- CD47 antibody, its ability to penetrate tissues is very limited and the antibody is not curative alone. Other investigators design experiments to explore additional measures to target the regulation of CD47 expression .Zi-ming Ye et.al [77]found Myocardial infarction associated transcript(MIAT) is increased in atherosclerotic plaque, the over-expression of MIAT increases the level of CD47 which is counteracted by the overexpression of miR-149-

Journal Pre-proof 5p.These findings indicate that the macrophage MIAT/miR-149-5p /CD47 signaling pathway serve as a critical key factor in the progression of necrotic atherosclerotic plaques. CD47 also participates in the immune response. Interestingly, Some researchers found that CD47 deficiency promotes the burden of atherosclerosis in CD47-knockout mice, possibly due to the increased proportion of IFN - γ producing CD90 + NK cells[68].This may be different from "don't eat me"

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signal involved in the process of atherosclerosis. Stent angioplasty is now the first line therapy for occlusive vascular disease, especially for

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coronary atherosclerotic disease. However, in-stent restenosis (ISR) presents a formidable

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problem, which is only partially addressed with drug-eluting stents (DES) [78]. The reaction to

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the foreign stent can be problematic and should not be neglected [79]. Immobilizing CD47 on

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stents can confer biocompatibility when appended to polymeric surfaces [74]. Specifically, stent surfaces can be modified with either recombinant CD47 or the peptide derived from CD47‟s Ig

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domain. CD47 modified stents significantly reduce restenosis compared to unmodified stents,

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which is attributed to CD47 binding to SIRPα, thus mediating downstream signaling to prevent inflammatory cell attachment [72, 73, 75]. Furthermore, as discussed above, upon binding to its

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ligand, TSP1, CD47 limits the release of NO and inhibits accumulation of cGMP [16, 44-47]. Also, CD47 was reported to accelerate replicative senescence and associated cycle arrest in endothelial cells or VSMCs [27], consequently impairing coronary arterial relaxation and decreasing blood flow. In contrast, inhibition of CD47 promotes angiogenesis and vascular integrity [49], which is beneficial for establishing collateral circulation in coronary arterial disease. 4.2CD47 inhibition protects against myocardial I/R injury

Journal Pre-proof Although the current stent therapy can significantly reduce the mortality of acute myocardial infarction, ischemia-reperfusion(I/R) injury aggravates myocardial injury and promotes myocardial remodeling. Therefore, it is necessary

to find out the measures to reduce the

ischemia-reperfusion injury. A recent study showed that myocardial I/R induces CD47 expression, which decreases eNOS activity and NO levels and triggers oxidative stress. In contrast, CD47 inhibition protects against myocardial I/R injury, probably due to eNOS

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activation and reduced oxidative stress [17]. Consistent with these observations, another study

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showed that CD47 expression is also up-regulated in dying myocytes after myocardial I/R, while

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inhibition of CD47 reduced cardiac inflammation and infarct size and improved cardiac contractile function. These effects were attributed to macrophage mediated phagocytosis of

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dying cardiomyocytes and suppression of CD47-SIRPα signaling [59]. With regard to

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cardiomyocytes(H9C2) in vitro, other researchers found that after hypoxia for 24 hours and increased, and the

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reoxygenation for 12 hours, the rate of oxidative stress and apoptosis

clearance rate of autophagy decreased, which can be reversed by CD47 down-regulation or

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blocking[50].Thus, CD47 may be an ideal target to reduce myocardial I/R injury.

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4.3 CD47 inhibition ameliorates pulmonary hypertension via TSP1-CD47 signaling Pulmonary arterial hypertension (PAH) is a chronic and fatal disease, and its underlying mechanisms have been under extensive investigation. Several recent studies have shown that TSP1 is significantly induced by hypoxia induced factor-2a (HIF-2a) as a result of the hypoxia associated with PAH [86-88], and CD47 is also up-regulated in PAH patients [42, 44]. Furthermore, CD47 is up-regulated in idiopathic lung fibrosis [58], which is an important pathological change accompanying PAH [89, 90]. Thus, activation of the CD47-TSP1 axis may inhibit NO release or reduce pulmonary arterial sensitivity to NO, or stimulate ROS generation

Journal Pre-proof leading to PAH linked vasodilation disorders [16, 41, 42, 44-47, 91]. Correspondingly, inhibition of CD47 can ameliorate or reverse PAH progression [92]. Collectively, the literature indicates that inhibition of CD47 is an attractive molecular target for PAH treatment. 4.4 CD47 inhibition delays the process of heart failure Heart failure is a disease with high morbidity and mortality. Researchers have been exploring how to reduce the occurrence and development of heart failure . Maryam et.al demonstrated

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that TSP1-CD47 signaling is up-regulated in left ventricular heart failure (LVHF), which in turn

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heightens LVHF due to enhanced histone deacetylase 3 (HDAC3) expression. More specifically,

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the TSP1-CD47 axis modulates cardiac myocyte Ca2+ influx by mediating calcium calmodulin

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dependent protein kinase II (CaMKII) function to increase HDAC3 expression, resulting in myocyte hypertrophy and left ventricular (LV) stiffness, while inhibition of CD47 improves

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cardiac function [80]. Another study show the similar result the lack of CD47 can alleviate

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isoproterenol induced cardiac remodeling, which may be achieved by inhibiting HDAC3 signaling, improving AMPK pathway and increasing autophagy clearance.[81].Moreover,

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activation of the TSP1-CD47 axis suppresses cMyc to up-regulate ET-1/ETA [42], causing

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cellular hypertrophy [82, 83]. Interestingly, investigators found that CD47 high expression improved implanted mesenchymal stromal cell (MSC) survival due to delayed cardiomyocyte phagocytosis [84] and decreased myocardial fibrosis via STAT-mediated signaling [85]. Therefore,CD47 may play an important role in heart failure. 5. CD47 as a therapeutic target So far, the researchers did lots of work in various species and strain, from micro-organisms to mammals, from animal experiments to pre-clinical experiments suggesting :1) CD47 regulates the phagocytic clearance and replication of the Plasmodium yoelii malaria parasite[93, 94]; 2)

Journal Pre-proof CD47 Modulates Immune Response to Virus[95, 96];3) CD47 deficiency attenuates LPSinduced acute lung injury and E. coli pneumonia in mice;4)application of anti-CD47 antibody slows the progress of diseases involving various human solid tumors and leukemias [12, 97, 98]. 5) the results from animal studies have also consistently shown the possible therapeutic value of the anti-CD47 antibody in treatment of CVDs [13, 75]. In this text, we have reviewed many articles and found that targeting of CD47 signaling may be a potentially promising therapeutic

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strategy to attenuate inflammation, improve ischemia, and reverse atherosclerotic plaque

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formation. A number of strategies are used to inhibit CD47, including antibody blockade [61],

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CD47-knockout [49] and RNA interference (RNAi) technology [17], all of which demonstrate

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comparable outcomes. However, most of the experiments are focus on animal experiments, including mouse , rat and so on. To our excitement, the humanized anti-CD47 antibody (Hu5F9-

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G4) is actively being developed and has been in phase Ⅰ clinical trials in patients with acute

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myeloid leukemia(NCT02678338).In terms of CVDs, there is no effective immunotherapy is available, although canakinumab (NCT01327846) and methotrexate (NCT01594333) have been

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clinically evaluated in patients with atherosclerosis.Thus,CD47 maybe a novel target to attenuate

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or reverse the development of CVDs. Nevertheless, further work is needed to elucidate the exact mechanisms underlying the role of CD47 in CVDs, and to further investigate the potential clinical applications of different techniques that can target CD47 to benefit patients suffering from CVDs. Such interactions across and within species, from low-lifes to senior-lifes , from mouse to human, are not yet clear.

Besides, the safety and effectiveness of drugs are equally important. Some researchers assert that blockade of anti-CD47 antibody was not found unacceptable toxicity, albeit with a temporary anemia in

Journal Pre-proof serrated animal [13, 38, 99] or in non-human primates[100]. Furthermore, Whether it is equally safe in human body still needs further confirmation.

6. Concluding remarks Although we have made significant progress in elucidating the complex mechanisms underlying CVDs, we have only really just begun to understand these mechanisms. Many questions still need to be answered. For example, what is the mechanistic network underlying

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CVDs promoted by activated CD47? What are the real benefits of suppressing CD47 for CVDs

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patients? CD47 deficient mice succumb to bacterial infections due to defects in granulocyte

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migration and activation of an integrin-dependent oxidative burst response [101]. Thus, will

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systemic suppression of CD47 in humans generate similar side effects? With more advances in

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the field and clinical trials, CD47 might be a promising target for treating CVDs.

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7. Acknowledgements

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This work was supported by the National Natural Science Foundation of China [81770374].

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