Publications by authors named "Xiangchao Ding"

15 Publications

  • Page 1 of 1

Cytosporone B (Csn-B), an NR4A1 agonist, attenuates acute cardiac allograft rejection by inducing differential apoptosis of CD4+T cells.

Int Immunopharmacol 2022 Jan 10;104:108521. Epub 2022 Jan 10.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

CD4+T cell-mediated acute rejection remains a major factor that affects the early survival of transplanted organs post-transplantation. Here, we reveal that nuclear receptor subfamily 4 Group A member 1 (Nr4A1) was upregulated during cardiac allograft rejection and that the increased Nr4A1 was primarily localized in intragraft-infiltrating CD4+T cells. Nr4A1 acts as a transcription factor with an important role in CD4+T cell apoptosis, differentiation and T cell dysfunction, which indicates that Nr4A1 may play a critical role in transplant rejection. Cytosporone B (Csn-B) is a naturally occurring agonist of Nr4A1, and the role of Csn-B in the physiological process of cardiac rejection is poorly defined. This study constructed an acute rejection model of abdominal heterotopic cardiac transplantation in mice and investigated whether Csn-B could attenuate acute transplant rejection by modulating the CD4+T lymphocyte response. The results showed that Csn-B prolonged murine cardiac allograft survival and reduced inflammation in allografts. Subsequently, it was confirmed that Csn-B functions by inducing non-Treg apoptosis and promoting Treg cell differentiation. Finally, we also confirmed that Csn-B attenuates acute rejection by directly targeting Nr4A1 in CD4+T cells. Our data suggest that Csn-B is a promising novel therapeutic approach for acute cardiac allograft rejection.
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http://dx.doi.org/10.1016/j.intimp.2022.108521DOI Listing
January 2022

Plasma extracellular vesicle delivery of miR-210-3p by targeting ATG7 to promote sepsis-induced acute lung injury by regulating autophagy and activating inflammation.

Exp Mol Med 2021 07 28;53(7):1180-1191. Epub 2021 Jul 28.

Department of Thoracic Surgery, Renmin Hospital of Wuhan University, 430060, Wuhan, P.R. China.

Extracellular vesicles (EVs) can be used for intercellular communication by facilitating the transfer of miRNAs from one cell to a recipient cell. MicroRNA (miR)-210-3p is released into the blood during sepsis, inducing cytokine production and promoting leukocyte migration. Thus, the current study aimed to elucidate the role of plasma EVs in delivering miR-210-3p in sepsis-induced acute lung injury (ALI). Plasma EVs were isolated from septic patients, after which the expression of various inflammatory factors was measured using enzyme-linked immunosorbent assay. Cell viability and apoptosis were measured via cell counting kit-8 and flow cytometry. Transendothelial resistance and fluorescein isothiocyanate fluorescence were used to measure endothelial cell permeability. Matrigel was used to examine the tubulogenesis of endothelial cells. The targeting relationship between miR-210-3p and ATG7 was assessed by dual-luciferase reporter assays. The expression of ATG7 and autophagy-related genes was determined to examine autophagic activation. A sepsis mouse model was established by cecal ligation and puncture (CLP)-induced surgery. The level of miR-210-3p was highly enriched in septic EVs. MiR-210-3p enhanced THP-1 macrophage inflammation, BEAS-2B cell apoptosis, and HLMVEC permeability while inhibiting angiogenesis and cellular activity. MiR-210-3p overexpression reduced ATG7 and LC3II/LC3I expression and increased P62 expression. Improvements in vascular density and autophagosome formation, increased ATG7 expression, and changes in the ratio of LC3II/LC3I were detected, as well as reduced P62 expression, in adenovirus-anti-miR-210-3p treated mice after CLP injury. Taken together, the key findings of the current study demonstrate that plasma EVs carrying miR-210-3p target ATG7 to regulate autophagy and inflammatory activation in a sepsis-induced ALI model.
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http://dx.doi.org/10.1038/s12276-021-00651-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333093PMC
July 2021

Inhibition of S-adenosyl-L-homocysteine hydrolase alleviates alloimmune response by down-regulating CD4 T-cell activation in a mouse heart transplantation model.

Ann Transl Med 2020 Dec;8(23):1582

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Transmethylation reactions play an important role on lymphocyte activation and function. S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitors prevent the feedback of transmethylation reactions by S-adenosyl-L-homocysteine (SAH) accumulation, a competitive antagonist of S-adenosylmethionine (SAM)-dependent methyltransferases. However, the role of SAH in solid organ transplantation is currently unclear.

Methods: A murine model of cardiac transplantation (BALB/C to C57B/6) was established to assess allograft survival, histology, and T cell infiltration. The reversible SAHH inhibitor, DZ2002, and irreversible SAHH inhibitor, adenosine dialdehyde (AdOx), were used to assess their immunosuppressive effects in murine cardiac transplantation, compared with mice with DMSO.

Results: Both SAHH inhibitors prolonged the survival of cardiac allografts and alleviated alloimmune response. Notably, AdOx and DZ2002 both eliminated frequencies of Th1 and Th17 in CD4 T cells in cardiac transplantation, and reduced the frequency of active CD4 T cell (CD44 CD62L). The irreversible SAHH inhibitor facilitated the differentiation of regulatory T cells (Tregs) and increased Bim expression. Furthermore, both SAHH inhibitors alleviated infiltration of CD4 T cells in cardiac allografts.

Conclusions: The SAHH inhibitors (AdOx and DZ2002) alleviates allograft rejection in cardiac transplantation by inhibition of CD4 T alloimmune response. SAHH inhibitors, especially DZ2002, is a promising complementary therapeutic agent in organ transplantation.
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http://dx.doi.org/10.21037/atm-20-2899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791210PMC
December 2020

PKM2 Activator TEPP-46 Attenuates Thoracic Aortic Aneurysm and Dissection by Inhibiting NLRP3 Inflammasome-Mediated IL-1β Secretion.

J Cardiovasc Pharmacol Ther 2020 07 23;25(4):364-376. Epub 2020 Apr 23.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: The development of thoracic aortic aneurysm and dissection (TAAD) is mediated by inflammasome activation, which exacerbates the secretion of pro-inflammatory cytokines, chemokines, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). The glycolytic enzyme pyruvate kinase M2 (PKM2) has shown a protective role against various disorders with an inflammatory basis, such as sepsis, tumorigenesis, and diabetic nephropathy. However, its potential role in TAAD has not been investigated so far.

Approach And Results: We analyzed aortic tissues from TAAD patients and the β-aminopropionitrile fumarate (BAPN)-induced mouse model of TAAD and observed elevated levels of PKM2 in the aortic lesions of both. Treatment with the PKM2 activator TEPP-46 markedly attenuated the progression of TAAD in the mouse model as demonstrated by decreased morbidity and luminal diameter of the aorta. In addition, the thoracic aortas of the BAPN-induced mice showed reduced monocytes and macrophages infiltration and lower levels of IL-1β, MMPs, and ROS when treated with TEPP-46. Furthermore, TEPP-46 treatment also suppressed the activation of the NOD-like receptor (NLR) family and pyrin domain-containing protein 3 (NLRP3) inflammasome by downregulating p-STAT3 and HIF1-α.

Conclusion: Pyruvate kinase M2 plays a protective role in TAAD development, and its activation is a promising therapeutic strategy against the progression of TAAD.
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http://dx.doi.org/10.1177/1074248420919966DOI Listing
July 2020

Trametinib alleviates lipopolysaccharide-induced acute lung injury by inhibiting the MEK-ERK-Egr-1 pathway.

Int Immunopharmacol 2020 Mar 8;80:106152. Epub 2020 Jan 8.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address:

Acute lung injury (ALI) is a devastating clinical disorder with a high mortality rate and for which there is no effective treatment. The main characteristic of ALI is uncontrolled inflammation, and macrophages play a critical role in the development of this disorder. Trametinib, an inhibitor of MAPK/ERK kinase (MEK) activity that possesses anti-inflammatory properties, has been approved for clinical use. Herein, the influence of trametinib and its underlying mechanism were investigated using a lipopolysaccharide (LPS)-induced murine ALI model. We found that trametinib treatment prevented the LPS-facilitated expression of proinflammatory mediators in macrophages, and this anti-inflammatory action was closely correlated with suppression of the MEK-ERK-early growth response (Egr)-1 pathway. Furthermore, trametinib treatment alleviated LPS-induced ALI in mice, and attenuated edema, proinflammatory mediator production, and neutrophil infiltration. Trametinib pretreatment also attenuated the MEK-ERK-Egr-1 pathway in lung tissues. In conclusion, these data demonstrate that trametinib pretreatment suppresses inflammation in LPS-activated macrophages in vitro and protects against murine ALI established by LPS administration in vivo through inhibition of the MEK-ERK-Egr-1 pathway. Therefore, trametinib might have therapeutic potential for ALI.
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http://dx.doi.org/10.1016/j.intimp.2019.106152DOI Listing
March 2020

TROVE2 strengthens the anti-inflammatory effect via macrophage polarization by estrogen induction in abdominal aortic aneurysm.

Life Sci 2020 Feb 19;242:117207. Epub 2019 Dec 19.

Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Abdominal Aortic Aneurysm (AAA) is a severe cardiovascular disease, with high mortality rate after acute rupture of blood vessels. However, the underlying pathogenesis of different morbidity between men and women remains unclear. In the present study, we first selected four datasets including 68 AAA and 32 control samples from published data on GEO database, and analyzed them by data mining. The integrative analysis found a total of 368 differentially expressed genes in E2-related AAA. Next, regulatory mechanism networks among these target genes were predicted, and four genes were identified as key nodes in the network, which play a major role in the immune system. We focused on the role of monocytes/macrophages in the development of cardiovascular diseases to further explore the role of estrogen in the polarization of monocytes/macrophage, the mRNA level of the four genes was validated by RT-PCR in RAW264.7 cells treated with β-estradiol (E2), diarylpropionitrile (DPN), 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), fulvestrant or vehicle. The results showed that the mRNA level and protein level of TROVE2 was significantly increased in estrogen or estrogen receptor agonist-treated groups. Moreover, estrogen affected the transformation of macrophages to M2 phenotype by detecting M1- and M2-related indicator genes at the mRNA level. Flow cytometry demonstrated that the TROVE2 deficiency led to a notable decrease in the level of M2 phenotype marker protein CD206. In conclusion, our results suggest that E2 can promote the expression of TROVE2, which is closely related to the M2-phenotype transformation of macrophages.
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http://dx.doi.org/10.1016/j.lfs.2019.117207DOI Listing
February 2020

BCL6 inhibitor FX1 attenuates inflammatory responses in murine sepsis through strengthening BCL6 binding affinity to downstream target gene promoters.

Int Immunopharmacol 2019 Oct 8;75:105789. Epub 2019 Aug 8.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Background: Sepsis occurs when an infection triggers deranged inflammatory responses. There exists no efficacious treatment for this condition. The transcriptional repressor B-cell Lymphoma 6 (BCL6) is known to act as an inhibitor of macrophage-mediated inflammatory responses. FX1, a novel specific BCL6 BTB inhibitor, is able to attenuate activity of B cell-like diffuse large B cell lymphoma (ABC-DLBCL). Nevertheless, the effect of FX1 in inflammatory responses and sepsis remains unknown.

Objectives: Here, we explored the effect and potential mechanisms of FX1 on the regulation of LPS-induced inflammatory responses in murine sepsis.

Method: Mice models of LPS-induced sepsis were monitored for survival rate following FX1 administration. ELISA was used to assess how FX1 administration affected pro-inflammatory cytokines present in macrophages exposed to LPS and in the serum of mice sepsis models. Flow cytometric analysis, Western blot and qRT-PCR were performed to evaluate differences in macrophages immune responses after FX1 pre-treatment. Finally, the affinity of BCL6 binding to downstream target genes was checked by ChIP.

Results: The survival rate of mice models of LPS-induced sepsis was improved in following FX1 administration. FX1 decreased the production of inflammatory cytokines, attenuated macrophage infiltration activities and reduced monocytes chemotaxis activities, all of which suggest that FX1 exert anti-inflammatory effects. Mechanistically, FX1 may enhance the affinity of BCL6 binding to downstream target pro-inflammatory genes.

Conclusions: These findings illustrated the anti-inflammatory properties and potential mechanisms of FX1 in sepsis caused by LPS. FX1 could potentially become a new immunosuppressive and anti-inflammatory drug candidate in sepsis therapy.
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http://dx.doi.org/10.1016/j.intimp.2019.105789DOI Listing
October 2019

Nucleotide-Binding Oligomerization Domain-Like Receptor Protein 3 Deficiency in Vascular Smooth Muscle Cells Prevents Arteriovenous Fistula Failure Despite Chronic Kidney Disease.

J Am Heart Assoc 2019 01;8(1):e011211

1 Department of Cardiovascular Surgery Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China.

Background The arteriovenous fistula ( AVF ) is the preferred hemodialysis access for patients with chronic kidney disease. Chronic kidney disease can increase neointima formation, which greatly contributes to AVF failure by an unknown mechanism. Our study aimed to determine the role of nucleotide-binding oligomerization domain-like receptor protein 3 ( NLRP 3) in neointima formation induced by experimental AVF s in the presence of chronic kidney disease. Methods and Results From our findings, NLRP 3 was upregulated in the intimal lesions of AVF s in both uremic mice and patients. Smooth muscle-specific knockout NLRP 3 mice exhibited markedly decreased neointima formation in the outflow vein of AVF s. Compared with primary vascular smooth muscle cells isolated from control mice, those isolated from smooth muscle-specific knockout NLRP 3 mice showed compromised proliferation, migration, phenotypic switching, and a weakened ability to activate mononuclear macrophages. To identify how NLRP 3 functions, several small-molecule inhibitors were used. The results showed that NLRP 3 regulates smooth muscle cell proliferation and migration through Smad2/3 phosphorylation rather than through caspase-1/interleukin-1 signaling. Unexpectedly, the selective NLRP 3-inflammasome inhibitor MCC 950 also repressed Smad2/3 phosphorylation and relieved chronic kidney disease-promoted AVF failure independent of macrophages. Conclusions Our findings suggest that NLRP 3 in vascular smooth muscle cells may play a crucial role in uremia-associated AVF failure and may be a promising therapeutic target for the treatment of AVF failure.
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http://dx.doi.org/10.1161/JAHA.118.011211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405733PMC
January 2019

Dual-Specificity Phosphatase 26 Protects Against Nonalcoholic Fatty Liver Disease in Mice Through Transforming Growth Factor Beta-Activated Kinase 1 Suppression.

Hepatology 2019 05;69(5):1946-1964

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Nonalcoholic fatty liver disease (NAFLD), which has a wide global distribution, includes different stages ranging from simple steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and liver cirrhosis according to the degree of severity. Chronic low-grade inflammation, insulin resistance, and lipid accumulation are the leading causes of NAFLD. To date, no effective medicine for NAFLD has been approved by governmental agencies. Our study demonstrated that the expression of dual-specificity phosphatase 26 (Dusp26), a member of the Dusp protein family, was decreased in the liver tissue of mice with hepatic steatosis and genetically obese (ob/ob) mice. In our study, hepatic steatosis, inflammatory responses, and insulin resistance were exacerbated in liver-specific Dusp26-knockout (KO) mice but ameliorated in liver-specific Dusp26-transgenic mice induced by a high-fat diet. In addition, the degree of liver fibrosis was aggravated in high-fat high-cholesterol diet-induced Dusp26-KO mice. We further found that the binding of Dusp26 to transforming growth factor beta-activated kinase 1 (TAK1) to block the phosphorylation of TAK1 regulated the TAK1-p38/c-Jun NH2-terminal kinase signaling axis to alleviate hepatic steatosis and metabolic disturbance. Conclusion: These findings suggest that Dusp26 is a good TAK1-dependent therapeutic target for NAFLD.
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http://dx.doi.org/10.1002/hep.30485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594223PMC
May 2019

ADAM23 in Cardiomyocyte Inhibits Cardiac Hypertrophy by Targeting FAK - AKT Signaling.

J Am Heart Assoc 2018 09;7(18):e008604

4 Department of Cardiovascular Surgery Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China.

Background Cardiac hypertrophy has been recognized as an important independent risk factor for the development of heart failure and increases the risk of cardiac morbidity and mortality. A disintegrin and metalloprotease 23 (ADAM23), a member of ADAM family, is involved in cancer and neuronal differentiation. Although ADAM23 is expressed in the heart, the role of ADAM23 in the heart and in cardiac diseases remains unknown. Methods and Results We observed that ADAM23 expression is decreased in both failing human hearts and hypertrophic mice hearts. Cardiac-specific conditional ADAM23-knockout mice significantly exhibited exacerbated cardiac hypertrophy, fibrosis, and dysfunction, whereas transgenic mice overexpressing ADAM23 in the heart exhibited reduced cardiac hypertrophy in response to pressure overload. Consistent results were also observed in angiotensin II -induced neonatal rat cardiomyocyte hypertrophy. Mechanistically, ADAM23 exerts anti-hypertrophic effects by specifically targeting the focal adhesion kinase-protein kinase B (FAK-AKT) signaling cascade. Focal adhesion kinase inactivation by inhibitor ( PF -562271) greatly reversed the detrimental effects in ADAM23-knockout mice subjected to aortic banding. Conclusion Altogether, we identified ADAM23 as a negative regulator of cardiac hypertrophy through inhibiting focal adhesion kinase-protein kinase B signaling pathway, which could be a promising therapeutic target for this malady.
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http://dx.doi.org/10.1161/JAHA.118.008604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222933PMC
September 2018

MicroRNA-21 Knockout Exacerbates Angiotensin II-Induced Thoracic Aortic Aneurysm and Dissection in Mice With Abnormal Transforming Growth Factor-β-SMAD3 Signaling.

Arterioscler Thromb Vasc Biol 2018 05 8;38(5):1086-1101. Epub 2018 Mar 8.

From the Department of Cardiovascular Surgery, Union Hospital (X.H., Z.Y., J.C., J.W., P.D., K.W., C.W., X.D., J.X.)

Objective: Thoracic aortic aneurysm and dissection (TAAD) are severe vascular conditions. Dysfunctional transforming growth factor-β (TGF-β) signaling in vascular smooth muscle cells and elevated angiotensin II (AngII) levels are implicated in the development of TAAD. In this study, we investigated whether these 2 factors lead to TAAD in a mouse model and explored the possibility of using microRNA-21 () for the treatment of TAAD.

Approach And Results: TAAD was developed in (mothers against decapentaplegic homolog 3) heterozygous (S3) mice infused with AngII. We found that p-ERK (phosphorylated extracellular regulated protein kinases)- and p-JNK (phosphorylated c-Jun N-terminal kinase)-associated was higher in TAAD lesions. We hypothesize that downregulation of mitigate TAAD formation. However, (S321) mice exhibited conspicuous TAAD formation after AngII infusion. The vascular wall was dilated, and aortic rupture occurred within 23 days during AngII infusion. We then examined canonical and noncanonical TGF-β signaling and found that knockout in S3 mice increased SMAD7 and suppressed canonical TGF-β signaling. Vascular smooth muscle cells lacking TGF-β signals tended to switch from a contractile to a synthetic phenotype. The silencing of with lentivirus prevented AngII-induced TAAD formation in S321 mice.

Conclusions: Our study demonstrated that knockout exacerbated AngII-induced TAAD formation in mice, which was associated with TGF-β signaling dysfunction. Therapeutic strategies targeting TAAD should consider unexpected side effects associated with alterations in TGF-β signaling.
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http://dx.doi.org/10.1161/ATVBAHA.117.310694DOI Listing
May 2018

A Disintegrin and Metalloprotease-22 Attenuates Hypertrophic Remodeling in Mice Through Inhibition of the Protein Kinase B Signaling Pathway.

J Am Heart Assoc 2018 01 22;7(2). Epub 2018 Jan 22.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Background: Severe cardiac hypertrophy can lead to cardiac remodeling and even heart failure in the end, which is a leading cause of cardiovascular disease-related mortality worldwide. A disintegrin and metalloprotease-22 (ADAM22), a member of the transmembrane and secreted metalloendopeptidase family, participates in many biological processes, including those in the cardiovascular system. However, there is no explicit information on whether ADAM22 can regulate the process of cardiac hypertrophy; the effects that ADAM22 exerts in cardiac hypertrophy remain elusive.

Methods And Results: We observed significantly increased ADAM22 expression in failing hearts from patients with dilated cardiomyopathy and hypertrophic cardiomyopathy; the same trend was observed in mice induced by transaortic constriction and in neonatal rat cardiomyocytes treated by angiotensin II. Therefore, we constructed both cardiac-specific ADAM22 overexpression and knockout mice. At 4 weeks after transaortic constriction, cardiac-specific ADAM22 knockout, by the CRISPR/Cas9 (clustered regularly interspaced palindromic repeat (CRISPR)-Cas9) system, deteriorated the severity of cardiac hypertrophy in mice, whereas cardiac-specific ADAM22 overexpression mitigated the degrees of cardiac hypertrophy in mice. Similarly, altered ADAM22 expression modulated the angiotensin II-mediated cardiomyocyte hypertrophy in neonatal rat cardiomyocytes. After screening several signaling pathways, we found ADAM22 played a role in inhibition of protein kinase B (AKT) activation. Under the cardiac-specific ADAM22 knockout background, AKT activation was enhanced in transaortic constriction-induced mice and angiotensin II-stimulated neonatal rat cardiomyocytes, with a severe degree of cardiac hypertrophy. Treatment of a specific AKT inhibitor attenuated the transaortic constriction-enhanced AKT activation and cardiac hypertrophy in mice.

Conclusions: The findings demonstrated that ADAM22 negatively regulates the AKT activation and the process of cardiac hypertrophy and may provide new insights into the pathobiological features of cardiac hypertrophy.
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http://dx.doi.org/10.1161/JAHA.117.005696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850139PMC
January 2018

Inhibition of intimal hyperplasia in murine aortic allografts by administration of a small-molecule TLR4 inhibitor TAK-242.

Sci Rep 2017 Nov 17;7(1):15799. Epub 2017 Nov 17.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Graft arteriosclerosis (GA) is the leading cause of late cardiac allograft dysfunction. The innate immune system plays a major role in GA, paprticularly Toll-like receptor 4 (TLR4) signaling. Here we characterized the role of TLR4 and its antagonist TAK-242 in a mouse model of GA. BALB/c (H-2d) donor aortas were transplanted into C57BL/6 (H-2b) recipients, and the mice received intraperitoneal injection of 3 or 10 mg/kg of TAK-242 or vehicle every other day for 1, 2, 4, 6, 8 and 12 weeks. With TAK-242 administration, intimal hyperplasia initially appeared at 2 weeks after transplantation, and TAK-242 postponed the progression of neointimal formation in allogeneic aortic grafts. TAK-242 treatment reduced CD68+ macrophage accumulation in the allografts, reduced the levels of ly-6C monocytes in peripheral blood, bone marrow and spleen, and downregulated proinflammatory cytokine and chemokine levels. Ex vivo we observed that TAK-242 could improve the graft microenvironment by interfering the Tck/Mφ IL12p70 and IFNγ axis, reducing CCL2-mediated migration of vascular smooth cells.
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http://dx.doi.org/10.1038/s41598-017-16160-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693917PMC
November 2017

Knockout of microRNA-155 ameliorates the Th1/Th17 immune response and tissue injury in chronic rejection.

J Heart Lung Transplant 2017 Feb 6;36(2):175-184. Epub 2016 May 6.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Medicine, Central Hospital of Wuhan, Wuhan, China; Department of Cardiovascular Surgery, Central Hospital of Wuhan, Wuhan, China. Electronic address:

Background: MicroRNAs (miRNAs) are integral for maintaining immune homeostasis and self-tolerance. The influence of miRNAs on T-cell differentiation and plasticity are critical in the development of chronic rejection of transplanted hearts. In this study, we sought to determine whether the knockout of miR-155 affects the development of cardiac allograft vasculopathy (CAV) in a murine model.

Methods: miRNA microarray and quantitative polymerase chain reaction (qPCR) analyses were performed for allograft neointimal lesion samples in chronic rejection. A model of heterotopic murine heart transplantation (bm12 to miR-155 or miR-155 mice) was then used to analyze allograft survival, histology, mRNA expression and T-cell sub-populations in spleens. The accelerated experiments were performed by intraperitoneal injection of either recombinant interleukin-17A or phosphate-buffered saline (PBS) after heart transplantation. For the competitive transfer experiments, CD4 splenocytes from wild-type (WT) or miR-155 mice were mixed and injected into Rag1 mice, and cardiac transplantation was performed after 24 hours. The differentiation of T-helper subsets (Th1/Th17/iTreg) was investigated in vitro.

Results: miR-155 mice showed resistance to cardiac rejection along with weakened T-cell-mediated inflammation, especially for Th17 cells. Recombinant IL-17A could restore this relieved injury. The competitive experiments implied that miR-155 plays a vital role in the stability of the Th17 phenotype. In vitro, we also demonstrated that miR-155 mice exhibit a defect in Th17 differentiation.

Conclusions: miR-155 regulates Th1/Th17-related inflammation in chronic cardiac rejection and may be a potential therapeutic target to attenuate cardiac allograft rejection. Despite advancements in immunosuppressive therapy, the immunologic mechanisms responsible for allograft rejection remain an important issue for both clinicians and researchers. Allograft rejection is a T-cell-dependent phenomenon and is critically dependent on inflammation mediated by CD4 Th subsets, including Th1, Th2, Th17, Th9 and regulatory T (Treg) cells.
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http://dx.doi.org/10.1016/j.healun.2016.04.018DOI Listing
February 2017

MicroRNA-155 Promotes the Directional Migration of Resident Smooth Muscle Progenitor Cells by Regulating Monocyte Chemoattractant Protein 1 in Transplant Arteriosclerosis.

Arterioscler Thromb Vasc Biol 2016 06 14;36(6):1230-9. Epub 2016 Apr 14.

From the Department of Vascular Surgery, The Clinical Medical College of Yangzhou University, Yangzhou, China (Y.S., Z.C.); Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Y.S., K.W., J.W., L.R., A.Z., X.H., P.D., C.W., Z.Y., X.D., J.C., J.X.); and Departments of Cardiovascular Medicine (P.Y., L.R., J.X.) and Cardiovascular Surgery (P.Y., L.R., J.X.), Central Hospital of Wuhan, Wuhan, China.

Objective: Smooth muscle-like cells are major cell components of transplant arteriosclerosis lesions. This study investigated the origin of the smooth muscle-like cells, the mechanisms responsible for their accumulation in the neointima, and the factors that drive these processes.

Approach And Results: A murine aortic transplantation model was established by transplanting miR-155(-/-) bone marrow cells into miR-155(+/+) mice. MicroRNA-155 was found to play a functional role in the transplant arteriosclerosis. Moreover, we found that the nonbone marrow-derived progenitor cells with markers of both early differentiated smooth muscles and stem cells in the allograft adventitia were smooth muscle progenitor cells. Purified smooth muscle progenitor cells expressed a mature smooth muscle cell marker when induced by platelet-derived growth factor-BB in vitro. In vivo, these cells could migrate into the intima from the adventitia and could contribute to the neointimal hyperplasia. The loss of microRNA-155 in bone marrow-derived cells decreased the concentration gradient of monocyte chemoattractant protein 1 between the intima and the adventitia of the allografts, which reduced the migration of smooth muscle progenitor cells from the adventitia into the neointima.

Conclusions: This study demonstrated that microRNA-155 promoted the directional migration of smooth muscle progenitor cells from the adventitia by regulating the monocyte chemoattractant protein 1 concentration gradient, which aggravated transplant arteriosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.115.306691DOI Listing
June 2016
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