Publications by authors named "Chuangyan Wu"

20 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

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

The importance of overweight in COVID-19: A retrospective analysis in a single center of Wuhan, China.

Medicine (Baltimore) 2020 Oct;99(43):e22766

Cancer center.

The aim of this study was to evaluate the association between overweight and severity, drug response, and clinical outcomes of novel coronavirus disease 2019 (COVID-19).In this retrospective cohort study, we reviewed medical records of 240 COVID-19 patients admitted to Union Hospital in Wuhan, China, between December 24, 2019, and March 25, 2020. Physical, clinical, laboratory, radiological characteristics, treatment, and outcome data were abstracted. Patients who were obese [body mass index (BMI) ≥28 kg/m], underweight (BMI < 18.5 kg/m), under 18 years old, pregnant, or still in hospital were excluded. Disease severity was classified as moderate or severe pneumonia based on the World Health Organization interim guidance. Overweight was defined as BMI ≥24 kg/m and <28 kg/m. Patients were followed for discharge or death through April 10, 2020. We used logistic regression models to identify risk factors for severe disease, Cox proportional hazard models to explore associations between medications and patient outcomes (discharge or in-hospital death), and Kaplan-Meier survival curves and Cox regression models to evaluate risk factors for in-hospital death.One-half of patients (120, 50.0%) had severe pneumonia, while nearly one-half (114, 47.5%) were overweight. Among patients over 45 years old, overweight patients had significantly lower rates of fatigue, higher rates of headache, and higher median C-reactive protein levels. Patients under 45 years old had higher rates of cough and myalgia and higher proportions of increased alanine aminotransferase and lactic dehydrogenase, as well as more pulmonary lobes involved in the pneumonia revealed by chest computed tomography scans. Overweight patients were at higher risk of developing severe pneumonia. Although weight was not a risk factor for in-hospital death, overweight patients showed different responses to medications compared with normal weight patients. Intravenous interferon-α, intravenous glucocorticoids, and antifungal drugs were associated with reduced mortality in overweight patients. Intravenous immunoglobulin, oseltamivir, and ribavirin were associated with reduced mortality in normal weight patients.Overweight is a worldwide health problem. We found overweight to be related to the COVID-19 severity but not to in-hospital death. Clinicians should be aware that overweight COVID-19 patients require increased attention for different clinical features and treatment response.
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http://dx.doi.org/10.1097/MD.0000000000022766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581045PMC
October 2020

Ribavirin therapy for severe COVID-19: a retrospective cohort study.

Int J Antimicrob Agents 2020 Sep 23;56(3):106114. Epub 2020 Jul 23.

Department of Respiratory and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address:

The aim of this study was to compare ribavirin therapy versus supportive therapy only for patients with severe coronavirus disease 2019 (COVID-19). A total of 115 patients with laboratory-confirmed COVID-19 were retrospectively analysed. All patients received supportive care as well as regular laboratory and clinical monitoring. The 115 patients comprised 44 patients who received intravenous ribavirin (treatment group) and 71 who did not (control group). Baseline laboratory and clinical characteristics were similar between the two groups. The negative conversion time for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR in the ribavirin group was 12.8 ± 4.1 days compared with 14.1 ± 3.5 days in the control group (P = 0.314). Moreover, 7/41 patients (17.1%) in the ribavirin group died compared with 17/69 (24.6%) in the control group (P = 0.475). Adverse effects were similar between the two groups. In conclusion, in patients with severe COVID-19, ribavirin therapy is not associated with improved negative conversion time for SARS-CoV-2 test and is not associated with an improved mortality rate. Further assessment in designed randomised controlled trials is recommended.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377772PMC
September 2020

Association between phthalate exposure and asthma risk: A meta-analysis of observational studies.

Int J Hyg Environ Health 2020 07 24;228:113539. Epub 2020 Apr 24.

Department of Clinical Laboratory, Guangdong Women and Children Hospital, Guangzhou, 511443, China. Electronic address:

Background: Phthalates are ubiquitously found in numerous environments and have been related to a variety of adverse health effects. Previous studies have suggested that phthalate exposure is associated with asthma risk in humans; however, such findings are inconsistent.

Methods: The aim of the present meta-analysis was to clarify the association between phthalate exposure and asthma risk. A literature search was conducted using PubMed, EMBASE and Web of Science for relevant studies published up to January 5, 2020. Fixed-effects or random-effects models were applied to combine the results, and several subgroup analyses were used to explore the sources of heterogeneity.

Results: A total of 14 studies containing more than 14,000 participants were included in the present study. A positive, significant association between mono-benzyl phthalate (MBzP) levels and asthma risk was found, and the overall odds ratio (OR) was 1.17 (95% confidence interval [CI]: 1.06-1.28, P-value for overall effect [P] = 0.001), with a low heterogeneity (P-value for heterogeneity [P] = 0.193, I = 23.6%). The pooled ORs for mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) concentrations were 1.13 (95% CI: 1.03-1.24, P = 0.011) and 1.20 (95% CI: 1.00-1.42, P = 0.045), respectively. Children with high levels of MBzP or mono-(carboxynonyl) phthalate (MCNP) were suggested to have increased odds of asthma compared to older populations. In the subgroup analysis by study location, an increased risk for asthma in relation to levels of the sum of di-2-ethylhexyl phthalate (ΣDEHP) was observed in European studies (OR = 1.16, 95% CI: 1.00-1.34, P = 0.048) compared to Asia and North America.

Conclusions: Urinary levels of MBzP, MEHHP, MECPP, MCNP, and DEHP were positively related to asthma risk. No significant association was observed for the other phthalate metabolites in relation to asthma risk. Further research is needed to verify these findings and shed light on the molecular mechanism by which phthalates are associated with asthma.
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http://dx.doi.org/10.1016/j.ijheh.2020.113539DOI 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

Cardiac rhabdomyomas with atrial septal defect and tricuspid insufficiency: A case report.

J Card Surg 2019 Oct 2;34(10):1123-1126. Epub 2019 Aug 2.

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

Primary cardiac tumors are very rare and generally benign. The most common type, cardiac rhabdomyoma, comprises 45% to 75% of primary cardiac tumors. Cardiac rhabdomyoma is a rare benign tumor that commonly presents with tuberous sclerosis. We present a case of an infant with multifocal cardiac rhabdomyomas with an atrial septal defect and tricuspid insufficiency and no sign of tuberous sclerosis. She was successfully treated with an operation, the treatment plan included mass resection, tricuspid annuloplasty, and closure of the patent foramen ovale. The right atrial lesion was resected entirely, while the lobulated lesion in the right ventricle was resected as two pieces. There was no evidence of recurrence 1 year after the surgery.
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http://dx.doi.org/10.1111/jocs.14191DOI Listing
October 2019

Deregulation of lncRNA-AC078883.3 and microRNA-19a is involved in the development of chemoresistance to cisplatin via modulating signaling pathway of PTEN/AKT.

J Cell Physiol 2019 12 20;234(12):22657-22665. Epub 2019 May 20.

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

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide. As a platinum-based chemotherapeutic drug, cisplatin has been used in the NSCLC treatment for over 30 years, and its effects are impaired by drug resistance. This study aimed to investigate the potential role of lncRNA-AC078883.3 in the development of chemoresistance against cisplatin. Real-time PCR, Western blot analysis, Immunohistochemistry (IHC) assay, bioinformatic analysis, and luciferase assay were collaboratively used to establish the lncRNA-AC078883.3/miR-19a/PTEN/AKT pathway. Also, the effect of cisplatin on cell proliferation was observed via an MTT assay. Furthermore, Cox regression and Kaplan-Meier analyses were used to study whether lncRNA-AC078883.3 is involved in the survival of NSCLC. Compared with the Cisplatin-Sensitive group, the Cisplatin-Resistance group exhibited lower levels of lncRNA-AC078883.3 and PTEN and higher levels of miR-19a and p-Akt. The growth rate of A549 and H460 cells and the IC of DPP in the Cisplatin-Resistance group were higher than those in the Cisplatin-S group. miR-19a contains a putative binding site of lncRNA-AC078883.3, which enabled the luciferase activity of wild-type lncRNA-AC078883.3 to be reduced by miR-19a. In addition, by directly targeting PTEN 3'-untranslated region (UTR), miR-19a repressed the luciferase activity of wild-type PTEN 3'-UTR. The median OS of patients with reduced lncRNA-AC078883.3 expression was longer than that of patients with higher lncRNA-AC078883.3 expression. Finally, compared with low lncRNA-AC078883.3-expression patients, the high lncRNA-AC078883.3-expression patients were associated with lower miR-19a expression and higher PTEN expression. Therefore, we suggested for the first time that the low expression of lncRNA-AC078883.3 contributed to the development of chemoresistance against cisplatin.
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http://dx.doi.org/10.1002/jcp.28832DOI Listing
December 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

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

MicroRNA-155 promotes neointimal hyperplasia through smooth muscle-like cell-derived RANTES in arteriovenous fistulas.

J Vasc Surg 2018 03;67(3):933-944.e3

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

Objective: Arteriovenous fistula (AVF) suffers from a high number of failures caused by insufficient outward remodeling and venous neointimal hyperplasia formation. The aim was to investigate the exact mechanism by which microRNA-155 (miR-155) in the outflow vein of AVF is regulated.

Methods: AVFs between the branch of the jugular vein and carotid artery in an end-to-end manner were created in C57BL/6 and miR-155 mice with a C57BL/6 background. The venous segments were harvested at day 7, 14, 21, and 28, and the AVFs were analyzed histologically and at a messenger RNA level using real-time quantitative polymerase chain reactions. The outflow vein of AVF and the normal great saphenous vein, collected from patients with chronic kidney disease and coronary artery bypass surgery, were analyzed by histologic and molecular biologic approaches.

Results: Venous neointimal hyperplasia is significantly alleviated in miR-155 mice, and the expression of several chemokines and cytokines in the vessel wall, including regulated on activation, normal T-cell expressed and secreted factor (RANTES), monocyte chemoattractant protein 1, and vascular endothelial growth factor, was inhibited. miR-155 promoted the RANTES expression of smooth muscle-like cells, which in turn facilitated cell proliferation and extracellular matrix production.

Conclusions: miR-155 enhances venous neointima formation through the autocrine and paracrine effects of smooth muscle-like cell-derived RANTES in a nuclear factor κB-dependent manner during the entire AVF process, especially at the advanced stage.
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http://dx.doi.org/10.1016/j.jvs.2017.02.046DOI Listing
March 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-150 Inhibits the Activation of Cardiac Fibroblasts by Regulating c-Myb.

Cell Physiol Biochem 2016 17;38(6):2103-22. Epub 2016 May 17.

Background/aims: Cardiac fibrosis is the primary cause of deteriorated cardiac function in various cardiovascular diseases. Numerous studies have demonstrated that microRNAs (miRNAs) are critical regulators of myocardial fibrosis. Specifically, many studies have reported that miR-150 is downregulated in cardiovascular diseases, such as acute myocardial infarction (AMI), myocardial hypertrophy and myocardial fibrosis. However, the exact role of miR-150 in these pathological processes remains unknown.

Methods: We used the transverse aortic constriction (TAC) mouse model to study the role of miR-150 in cardiac fibrosis induced by pressure overload. After the TAC operation, qRT-PCR was used to measure the expression profiles of miR-150 in left ventricle tissues and populations of primary heart cell types. Then, we used both miR-150 knockout mice and wild type (WT) mice in the TAC model. Changes in cardiac function and pathology were measured using transthoracic echocardiography and pathological analysis, respectively. Furthermore, we predicted the target of miR-150 in cardiac fibroblasts (CFs) and completed in vitro CF transfection experiments using miR-150 analogs and siRNA corresponding to the predicted target.

Results: We observed decreased expression levels of miR-150 in hearts suffering pressure overload, and these levels decreased more sharply in CFs than in cardiomyocytes. In addition, the degrees of cardiac function deterioration and cardiac fibrosis in miR-150-/- mice were more severe than were those in WT mice. By transfecting CFs with an miR-150 analog in vitro, we observed that miR-150 inhibited cardiac fibroblast activation. We predicted that the transcription factor c-Myb was the target of miR-150 in CFs. Transfecting CFs with c-Myb siRNA eliminated the effects of an miR-150 inhibitor, which promoted CF activation.

Conclusion: These findings reveal that miR-150 acts as a pivotal regulator of pressure overload-induced cardiac fibrosis by regulating c-Myb.
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http://dx.doi.org/10.1159/000445568DOI 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

MicroRNA-150 protects the heart from injury by inhibiting monocyte accumulation in a mouse model of acute myocardial infarction.

Circ Cardiovasc Genet 2015 Feb 2;8(1):11-20. Epub 2014 Dec 2.

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

Background: MicroRNAs (miRs) and inflammatory monocytes participate in many cardiac pathophysiological processes including acute myocardial infarction (AMI). Recently, we observed that miR-150 is downregulated in injured mouse plasma after AMI as well as in human infarcted monocytes. However, the precise functional role of miR-150 in response to AMI remains unknown.

Methods And Results: In a mouse model of AMI and in human subjects with AMI, we found that miR-150 expression was reduced in monocytes. In vitro studies showed that ectopic expression of miR-150 markedly reduced monocyte migration and proinflammatory cytokine production, whereas blockade of miR-150 had opposing effects. In vivo studies showed that overexpression of miR-150 in mice resulted in improved cardiac function, reduced myocardial infarction size, inhibition of apoptosis, and reduced inflammatory Ly-6C(high) monocyte invasion levels after AMI. Wild-type mice transplanted with miR-150 null (-/-) bone marrow cells could reverse this protective effect. Mechanistic studies demonstrated that miR-150 inhibited the expression of chemokine receptor 4 (CXCR4), thereby promoting monocyte migration.

Conclusions: Our findings indicate that miR-150 acts as a critical regulator of monocyte cell migration and production of proinflammatory cytokines, leading to cardioprotective effects against AMI-induced injury. Thus, miR-150 may be a suitable target for therapeutic intervention in the setting of ischemic heart disease.
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http://dx.doi.org/10.1161/CIRCGENETICS.114.000598DOI Listing
February 2015

Inhibition of intimal hyperplasia in murine aortic allografts by the oral administration of the transforming growth factor-beta receptor I kinase inhibitor SD-208.

J Heart Lung Transplant 2014 Jun 21;33(6):654-61. Epub 2014 Feb 21.

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

Background: Transforming growth factor-beta (TGF-β) plays a significant role in the pathogenesis of the intimal hyperplasia of transplant arteriosclerosis (TA). The aim of this study was to evaluate the efficacy of an oral inhibitor of TGF-β receptor I kinase (SD-208) on the development of TA.

Methods: BALB/c (H-2(d)) donor aortas were transplanted into C57BL/6 (H-2(b)) recipients, and the mice then received different doses (40 or 60 mg/kg) of SD-208 or control vehicle by daily gavage for 8 weeks. The grafts were analyzed by histology and morphometry at 1, 2, 4, 6 and 8 weeks after transplantation. The effects of TGF-β and SD-208 on neointimal smooth muscle-like cell (SMLC) and vascular smooth muscle cell (VSMC) proliferation and migration were evaluated, and the expression levels of Smad3, P-Smad3, connective tissue growth factor (CTGF) and collagen I were determined by in vitro experiments.

Results: The intimal hyperplasia of the SD-208-treated group was significantly reduced compared with the vehicle-treated control group (32% and 48% reduction for 40 mg/kg and 60 mg/kg SD-208 compared with the controls, respectively [n = 5], p < 0.05). SD-208 reduced SMLC proliferation and the production of intimal collagen by 21% and 75%, respectively, in the grafts. SD-208 also abolished the promoting effect of TGF-β on SMLC proliferation and migration but did not affect TGF-β inhibition of VSMCs in vitro. CTGF, a protein downstream of TGF-β, was downregulated with the inhibition of Smad3 phosphorylation by SD-208, both in vitro and in vivo. Moreover, we found that the endogenous Smad3 in SMLCs was upregulated from 2 weeks after transplantation and was 64% higher than in VSMCs at 8 weeks.

Conclusion: These results demonstrate that SD-208 can effectively reduce the formation of intimal hyperplasia of TA in the murine aortic allograft model.
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http://dx.doi.org/10.1016/j.healun.2014.02.020DOI Listing
June 2014
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