Publications by authors named "Qingbo Xu"

270 Publications

The binding of autotaxin to integrins mediates hyperhomocysteinemia-potentiated platelet activation and thrombosis.

Blood Adv 2021 Sep 24. Epub 2021 Sep 24.

Peking University, Beijing, China.

Hyperhomocysteinemia (HHcy) is associated with an exaggerated platelet thrombotic response at sites of vascular injury. Here, a human medical examination report showed that elevated human plasma Hcy levels were positively correlated with enhanced blood coagulation and platelet activity, suggesting that humans with HHcy are more prone to thrombus formation at the sites of vascular injury. Accordingly, we observed accelerated platelet activation, primary hemostasis, and thrombus formation both in acute and chronic HHcy ApoE-/- mice. Upon Hcy administration in C57BL/6J mice, platelet aggregation, spreading, and clot retraction were markedly promoted. More importantly, homocysteine (Hcy) increased the affinity of platelet integrin αIIbβ3 with ligands and enhanced integrin outside-in signaling by promoting membrane phosphatidylserine (PS) exposure in vitro. Mechanistically, lipidomics analysis showed that lysophosphatidylcholines were the primary metabolites leading to clustering of HHcy-stimulated platelets. Cytosolic phospholipase A2 (cPLA2) activity and autotaxin (ATX, a secreted lysophospholipase D) secretion were upregulated by Hcy, leading to membrane phospholipid hydrolysis and PS exposure. Moreover, secreted ATX directly interacted with integrin β3. Inhibitors of cPLA2 and ATX activity blocked integrin αIIbβ3 outside-in signaling and thrombosis in HHcy ApoE-/- mice. This study identifies a novel mechanism by which HHcy promotes platelet membrane phospholipid catabolism and extracellular ATX secretion to activate integrin outside-in signaling, consequently to exaggerate thrombosis. This study reveals an innovative approach to treat HHcy-related thrombotic diseases.
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http://dx.doi.org/10.1182/bloodadvances.2021004572DOI Listing
September 2021

Pharmacological inhibition of arachidonate 12-lipoxygenase ameliorates myocardial ischemia-reperfusion injury in multiple species.

Cell Metab 2021 Oct 17;33(10):2059-2075.e10. Epub 2021 Sep 17.

Gannan Institute of Translational Medicine, Ganzhou 341000, China.

Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomes of revascularization after myocardial infarction. To identify the fundamental regulator of reperfusion injury, we performed metabolomics profiling in plasma of individuals before and after revascularization and identified a marked accumulation of arachidonate 12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potent induction of 12-HETE proceeded by reperfusion was conserved in post-MIR in mice, pigs, and monkeys. While genetic inhibition of Alox12 protected mouse hearts from reperfusion injury and remodeling, Alox12 overexpression exacerbated MIR injury. Remarkably, pharmacological inhibition of ALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly, ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and production of 12-HETE but also by its suppression of AMPK activity via a direct interaction with its upstream kinase TAK1. Taken together, our study demonstrates that ALOX12 is a novel AMPK upstream regulator in the post-MIR heart and that it represents a conserved therapeutic target for the treatment of myocardial reperfusion injury.
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http://dx.doi.org/10.1016/j.cmet.2021.08.014DOI Listing
October 2021

Nonbone Marrow CD34 Cells Are Crucial for Endothelial Repair of Injured Artery.

Circ Res 2021 Oct 3;129(8):e146-e165. Epub 2021 Sep 3.

Department of Cardiology and Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China. (S. Sun, M. Yang, Q. Chen, L. Zhang).

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.121.319494DOI Listing
October 2021

Deficiency of peroxisome proliferator-activated receptor α attenuates apoptosis and promotes migration of vascular smooth muscle cells.

Biochem Biophys Rep 2021 Sep 28;27:101091. Epub 2021 Jul 28.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education; Beijing, China.

Peroxisome proliferator-activated receptor (PPAR) α is widely expressed in the vasculature and has pleiotropic and lipid-lowering independent effects, but its role in the growth and function of vascular smooth muscle cells (VSMCs) during vascular pathophysiology is still unclear. Herein, VSMC-specific PPARα-deficient mice ( ) were generated by Cre-LoxP site-specific recombinase technology and VSMCs were isolated from mice aorta. PPARα deficiency attenuated VSMC apoptosis induced by angiotensin (Ang) II and hydrogen peroxide, and increased the migration of Ang II-challenged cells.
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http://dx.doi.org/10.1016/j.bbrep.2021.101091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339143PMC
September 2021

Application of genetic cell-lineage tracing technology to study cardiovascular diseases.

J Mol Cell Cardiol 2021 07 19;156:57-68. Epub 2021 Mar 19.

Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address:

Cardiovascular diseases are leading causes that threaten people's life. To investigate cells that are involved in disease development and tissue repair, various technologies have been introduced. Among these technologies, lineage tracing is a powerful tool to track the fate of cells in vivo, providing deep insights into cellular behavior and plasticity. In cardiac diseases, newly formed cardiomyocytes and endothelial cells are found from proliferation of local cells, while fibroblasts and macrophages are originated from diverse cell sources. Similarly, in response to vascular injury, various sources of cells including media smooth muscle cells, endothelium, resident progenitors and bone marrow cells are involved in lesion formation and/or vessel regeneration. In summary, current review summarizes the development of lineage tracing techniques and their utilizations in investigating roles of different cell types in cardiovascular diseases.
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http://dx.doi.org/10.1016/j.yjmcc.2021.03.006DOI Listing
July 2021

Perivascular tissue stem cells are crucial players in vascular disease.

Free Radic Biol Med 2021 03 5;165:324-333. Epub 2021 Feb 5.

Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, China. Electronic address:

Perivascular tissue including adipose layer and adventitia have been considered to play pivotal roles in vascular development and disease progression. Recent studies showed that abundant stem/progenitorcells (SPCs) are present in perivascular tissues. These SPCs exhibit capability to proliferate and differentiate into specific terminal cells. Adult perivascular SPCs are quiescent in normal condition, once activated by specific molecules (e.g., cytokines), they migrate toward the lumen side where they differentiate into both smooth muscle cells (SMCs) and endothelial cells (ECs), thus promoting intima hyperplasia or endothelial regeneration. In addition, perivascular SPCs can also regulate vascular diseases via other ways including but not limited to paracrine effects, matrix protein modulation and microvessel formation. Perivascular SPCs have also been shown to possess therapeutic potentials due to the capability to differentiate into vascular cells and regenerate vascular structures. This review summarizes current knowledge on resident SPCs features and discusses the potential benefits of SPCs therapy in vascular diseases.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.02.005DOI Listing
March 2021

Development and validation of a risk score using complete blood count to predict in-hospital mortality in COVID-19 patients.

Med (N Y) 2021 Apr 8;2(4):435-447.e4. Epub 2021 Jan 8.

Humanitas Clinical and Research Hospital IRCCS, Rozzano-Milan, Italy.

Background: To develop a sensitive risk score predicting the risk of mortality in patients with coronavirus disease 2019 (COVID-19) using complete blood count (CBC).

Methods: We performed a retrospective cohort study from a total of 13,138 inpatients with COVID-19 in Hubei, China, and Milan, Italy. Among them, 9,810 patients with 2 CBC records from Hubei were assigned to the training cohort. CBC parameters were analyzed as potential predictors for all-cause mortality and were selected by the generalized linear mixed model (GLMM).

Findings: Five risk factors were derived to construct a composite score (PAWNN score) using the Cox regression model, including platelet counts, age, white blood cell counts, neutrophil counts, and neutrophil:lymphocyte ratio. The PAWNN score showed good accuracy for predicting mortality in 10-fold cross-validation (AUROCs 0.92-0.93) and subsets with different quartile intervals of follow-up and preexisting diseases. The performance of the score was further validated in 2,949 patients with only 1 CBC record from the Hubei cohort (AUROC 0.97) and 227 patients from the Italian cohort (AUROC 0.80). The latent Markov model (LMM) demonstrated that the PAWNN score has good prediction power for transition probabilities between different latent conditions.

Conclusions: The PAWNN score is a simple and accurate risk assessment tool that can predict the mortality for COVID-19 patients during their entire hospitalization. This tool can assist clinicians in prioritizing medical treatment of COVID-19 patients.

Funding: This work was supported by National Key R&D Program of China (2016YFF0101504, 2016YFF0101505, 2020YFC2004702, 2020YFC0845500), the Key R&D Program of Guangdong Province (2020B1111330003), and the medical flight plan of Wuhan University (TFJH2018006).
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http://dx.doi.org/10.1016/j.medj.2020.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831644PMC
April 2021

Cartilage oligomeric matrix protein is an endogenous β-arrestin-2-selective allosteric modulator of AT1 receptor counteracting vascular injury.

Cell Res 2021 Jul 28;31(7):773-790. Epub 2021 Jan 28.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China.

Compelling evidence has revealed that biased activation of G protein-coupled receptor (GPCR) signaling, including angiotensin II (AngII) receptor type 1 (AT1) signaling, plays pivotal roles in vascular homeostasis and injury, but whether a clinically relevant endogenous biased antagonism of AT1 signaling exists under physiological and pathophysiological conditions has not been clearly elucidated. Here, we show that an extracellular matrix protein, cartilage oligomeric matrix protein (COMP), acts as an endogenous allosteric biased modulator of the AT1 receptor and its deficiency is clinically associated with abdominal aortic aneurysm (AAA) development. COMP directly interacts with the extracellular N-terminus of the AT1 via its EGF domain and inhibits AT1-β-arrestin-2 signaling, but not Gq or Gi signaling, in a selective manner through allosteric regulation of AT1 intracellular conformational states. COMP deficiency results in activation of AT1a-β-arrestin-2 signaling and subsequent exclusive AAA formation in response to AngII infusion. AAAs in COMP or ApoE mice are rescued by AT1a or β-arrestin-2 deficiency, or the application of a peptidomimetic mimicking the AT1-binding motif of COMP. Explorations of the endogenous biased antagonism of AT1 receptor or other GPCRs may reveal novel therapeutic strategies for cardiovascular diseases.
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http://dx.doi.org/10.1038/s41422-020-00464-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249609PMC
July 2021

Single-cell transcriptomics uncovers phenotypic alterations in the monocytes in a Chinese population with chronic cadmium exposure.

Ecotoxicol Environ Saf 2021 Mar 11;211:111881. Epub 2021 Jan 11.

Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China; Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China. Electronic address:

Background: Cadmium is the most prevalent form of heavy metal contaminant globally and its exposure rises serious health concern. Chronic exposure to cadmium causes immune disturbances. However, few studies have addressed how it affects circulating immune cells, one of the most essential elements for the host defense system, at both population and molecular level. Therefore, this is the first single-cell transcriptomic analysis of the response of the human circulating immune system to plasma cadmium level.

Methods: We conducted a cross-sectional study in Hunan province, which has the highest level of cadmium land contamination in China. A total of 3283 individuals were eligible for analyzing the association between plasma cadmium levels and the monocyte counts and its subgroups. Another 780 individuals were assigned for validation. Thirty propensity-matched individuals without chronic disease from the lowest- and highest-quartile groups according to serum cadmium levels were selected for single-cell RNA sequencing (scRNA-seq) and flow cytometry analyses. Moreover, the monocyte phenotypic alterations in the heavy metal-exposed population were validated with a cecal ligation and puncture sepsis mouse model.

Results: From August 2016 to July 2017, we conducted a cross-sectional study to identify phenotypic alterations in peripheral immune cells in cadmium polluted areas in China. Monocyte percentages were negatively associated with plasma cadmium levels in multivariable linear regression analysis. Peripheral blood mononuclear cell scRNA-seq revealed that the CD14 monocyte subset was dramatically reduced in the highest-quartile cadmium-exposed group. Moreover, we assessed different hallmarks of immune cell dysfunction-such as host defense capability, apoptotic signaling, cellular diversity and malignant gene expression in monocytes. Importantly, cadmium induced phenotypic alterations in the immune system were validated in the cecal ligation and puncture sepsis mouse model, in which chronic exposure to cadmium not only increased the death rate but also decreased monocyte numbers and the ability to clear bacterial infections.

Conclusion: This transcriptomic analysis provides molecular information about how the most important hallmarks of immune cell dysfunction are affected by plasma cadmium level. The significant phenotypic alterations in monocytes serving as early indicators of increased susceptibility to infectious and malignant diseases.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111881DOI Listing
March 2021

The Neutrophil-to-Lymphocyte Ratio Determines Clinical Efficacy of Corticosteroid Therapy in Patients with COVID-19.

Cell Metab 2021 02 5;33(2):258-269.e3. Epub 2021 Jan 5.

Department of Neonatology, Renmin Hospital of Wuhan University, Wuhan, China.

Corticosteroid therapy is now recommended as a treatment in patients with severe COVID-19. But one key question is how to objectively identify severely ill patients who may benefit from such therapy. Here, we assigned 12,862 COVID-19 cases from 21 hospitals in Hubei Province equally to a training and a validation cohort. We found that a neutrophil-to-lymphocyte ratio (NLR) > 6.11 at admission discriminated a higher risk for mortality. Importantly, however, corticosteroid treatment in such individuals was associated with a lower risk of 60-day all-cause mortality. Conversely, in individuals with an NLR ≤ 6.11 or with type 2 diabetes, corticosteroid treatment was not associated with reduced mortality, but rather increased risks of hyperglycemia and infections. These results show that in the studied cohort corticosteroid treatment is associated with beneficial outcomes in a subset of COVID-19 patients who are non-diabetic and with severe symptoms as defined by NLR.
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http://dx.doi.org/10.1016/j.cmet.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832609PMC
February 2021

Manganese porphyrin-based metal-organic framework for synergistic sonodynamic therapy and ferroptosis in hypoxic tumors.

Theranostics 2021 1;11(4):1937-1952. Epub 2021 Jan 1.

National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.

Development of efficient therapeutic strategy to incorporate ultrasound (US)-triggered sonodynamic therapy (SDT) and ferroptosis is highly promising in cancer therapy. However, the SDT efficacy is severely limited by the hypoxia and high glutathione (GSH) in the tumor microenvironment, and ferroptosis is highly associated with reactive oxygen species (ROS) and GSH depletion. A manganese porphyrin-based metal-organic framework (Mn-MOF) was constructed as a nanosensitizer to self-supply oxygen (O) and decrease GSH for enhanced SDT and ferroptosis. and analysis, including characterization, O generation, GSH depletion, ROS generation, lipid peroxidation, antitumor efficacy and tumor immune microenvironment were systematically evaluated. Mn-MOF exhibited catalase-like and GSH decreasing activity . After efficient internalization into cancer cells, Mn-MOF persistently catalyzed tumor-overexpressed HO to produce O to relieve tumor hypoxia and decrease GSH and GPX4, which facilitated the formation of ROS and ferroptosis to kill cancer cells upon US irradiation in hypoxic tumors. Thus, strong anticancer and anti-metastatic activity was found in H22 and 4T1 tumor-bearing mice after a single administration of Mn-MOF upon a single US irradiation. In addition, Mn-MOF showed strong antitumor immunity and improved immunosuppressive microenvironment upon US irradiation by increasing the numbers of activated CD8 T cells and matured dendritic cells and decreaing the numbers of myeloid-derived suppressor cells in tumor tissues. Mn-MOF holds great potential for hypoxic cancer therapy.
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http://dx.doi.org/10.7150/thno.45511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778611PMC
August 2021

Design, synthesis biological activity, and docking of novel fluopyram derivatives containing guanidine group.

Bioorg Med Chem 2021 01 8;29:115846. Epub 2020 Nov 8.

Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, P.R. China. Electronic address:

Succinate dehydrogenase (SDH), a crucial bridge enzyme between the respiratory electron transfer chain and tricarboxylic acid (or Krebs) cycle, has been identified as an ideal target for the development of effective fungicide. In this study, a series of 24 novel SDH inhibitors (SDHIs) were designed, synthesized, and characterized by H NMR, C NMR, and HRMS. In vitro fungicidal activity experiments, most of the compounds exhibited broad-spectrum antifungal activities against five plant pathogenic fungi. Compounds 9j and 9k showed excellent activities against Pythium aphanidermatum with EC values of 9.93 mg/L and 10.50 mg/L, respectively, which were superior to the lead compound Fluopyram with an EC value of 19.10 mg/L. Furthermore, the toxicity of these compounds was also tested against Meloidogyne incognita J2 nematodes. The results indicated that compound 9x exhibited moderate nematicidal activity (LC/48 h = 71.02 mg/L). Molecular docking showed that novel guanidine amide of 9j formed hydrogen bonds with crucial residues, which was crucial to the binding of an inhibitor and SDH. This present work indicates that these derivatives may serve as novel potential fungicides targeting SDH.
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http://dx.doi.org/10.1016/j.bmc.2020.115846DOI Listing
January 2021

Different Roles of Stem/Progenitor Cells in Vascular Remodeling.

Antioxid Redox Signal 2021 Jul 19;35(3):192-203. Epub 2021 Jan 19.

Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Since the discovery of vascular stem cells, there has been considerable advancement in comprehending the nature and functions of these cells. Due to their differentiation potential to repair endothelial cells and to participate in lesion formation during vascular remodeling, it is crucial to elucidate vascular stem cell behaviors and the mechanisms underlying this process, which could provide new chances for the design of clinical therapeutic application of stem cells. Over the past decades, major progress has been made on progenitor/vascular stem cells in the field of cardiovascular research. Vascular stem cells are mostly latent in their niches and can be bioactivated in response to damage and get involved in endothelial repair and smooth muscle cell aggregation to generate neointima. Accumulating evidence has been shown recently, using genetic lineage tracing mouse models, to particularly provide solutions to the nature of vascular stem cells and to monitor both cell migration and the process of differentiation during physiological angiogenesis and in vascular diseases. This article reviews and summarizes the current research progress of vascular stem cells in this field and highlights future prospects for stem cell research in regenerative medicine. Despite recent advances and achievements of stem cells in cardiovascular research, the nature and cell fate of vascular stem cells remain elusive. Further comprehensive studies using new techniques including genetic cell lineage tracing and single-cell RNA sequencing are essential to fully illuminate the role of stem cells in vascular development and diseases. 35, 192-203.
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http://dx.doi.org/10.1089/ars.2020.8199DOI Listing
July 2021

Lymphatics in Cardiovascular Disease.

Arterioscler Thromb Vasc Biol 2020 11 21;40(11):e275-e283. Epub 2020 Oct 21.

From the Department of Cardiology, The First Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China.

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http://dx.doi.org/10.1161/ATVBAHA.120.314735DOI Listing
November 2020

Effect of N-acetylcysteine on prevention of contrast-associated acute kidney injury in patients with STEMI undergoing primary percutaneous coronary intervention: a systematic review and meta-analysis of randomised controlled trials.

BMJ Open 2020 10 16;10(10):e039009. Epub 2020 Oct 16.

Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

Objective: Several studies evaluating the preventive effect of N-acetylcysteine (NAC) on contrast-associated acute kidney injury (CA-AKI) among patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) have suggested inconsistent results and that a systematic review and meta-analysis should be performed.

Design: Systematic review and meta-analysis.

Data Sources: PubMed, MEDLINE, EMBASE, ClinicalTrials.gov and the Cochrane Central databases were searched from inception to 15 November 2019.

Eligibility Criteria: Randomised controlled trials assessing use of NAC compared with non-use of NAC (eg, placebo) in preventing CA-AKI in patients with STEMI following PPCI were included.

Data Synthesis: Relative risks with 95% CIs were pooled using a random-effects model. Evidence level of conclusions was assessed by Cochrane GRADE measure.

Results: Seven trials including 1710 patients were identified. Compared with non-use of NAC, use of NAC significantly reduced the incidence of CA-AKI by 49% (risk ratio (RR) 0.51, 95% CI 0.31 to 0.82, p<0.01) and all-cause in-hospital mortality by 63% (RR 0.37, 95% CI 0.17 to 0.79, p=0.01). The estimated effects on the requirement for dialysis (RR 0.61, 95% CI 0.11 to 3.38, p=0.24) were not statistically significant. Trial sequential analysis confirmed the true positive of NAC in reducing risk of CA-AKI. Subgroup analyses suggested that the administration of NAC had greater benefits in patients with renal dysfunction and in those receiving oral administration and higher dosage of NAC.

Conclusions: NAC intake reduces the risk of CA-AKI and all-cause in-hospital mortality in patients with STEMI undergoing PPCI. The estimated potential benefit of NAC in preventing dialysis was ambiguous, and further high-quality studies are needed.

Prospero Registration Number: CRD42020155265.
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http://dx.doi.org/10.1136/bmjopen-2020-039009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569944PMC
October 2020

Stem/Progenitor Cells and Pulmonary Arterial Hypertension.

Arterioscler Thromb Vasc Biol 2021 01 8;41(1):167-178. Epub 2020 Oct 8.

Department of Cardiology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (X.P., L.D., Y.H., Q.X.).

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by endothelial dysfunction and vascular remodeling. Despite significant advancement in our understanding of the pathogenesis of PAH in recent years, treatment options for PAH are limited and their prognosis remains poor. PAH is now seen as a severe pulmonary arterial vasculopathy with structural changes driven by excessive vascular proliferation and inflammation. Perturbations of a number of cellular and molecular mechanisms have been described, including pathways involving growth factors, cytokines, metabolic signaling, elastases, and proteases, underscoring the complexity of the disease pathogenesis. Interestingly, emerging evidence suggests that stem/progenitor cells may have an impact on disease development and therapy. In preclinical studies, stem/progenitor cells displayed an ability to promote endothelial repair of dysfunctional arteries and induce neovascularization. The stem cell-based therapy for PAH are now under active investigation. This review article will briefly summarize the updates in the research field, with a special focus on the contribution of stem/progenitor cells to lesion formation via influencing vascular cell functions and highlight the potential clinical application of stem/progenitor cell therapy to PAH.
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http://dx.doi.org/10.1161/ATVBAHA.120.315052DOI Listing
January 2021

Experimental evidence and network pharmacology-based analysis reveal the molecular mechanism of Tongxinluo capsule administered in coronary heart diseases.

Biosci Rep 2020 10;40(10)

Maoming People's Hospital of Guangdong Province, No. 101 Weimin Road, Maonan District, Maoming City, Guangdong 525000, China.

Background: Tongxinluo (TXL) capsule, a polypharmacy derived from traditional Chinese medicine (TCM), has been widely used in coronary heart disease (CHD), while the underlying mechanism of TXL capsule is still unclear. The present study aimed at investigating the underlying mechanism of TXL acting on CHD patients and providing substantial evidence in molecular evidence by means of a network pharmacological analysis.

Method: Active compounds and targeted genes of TXL were retrieved from TCM systems pharmacology (TCMSP) and TCM integrative database (TCMID). CHD and coronary artery disease were treated as search queries in GeneCards and Online Mendelian Inheritance in Man (OMIM) databases to obtain disease-related genes. Visualization of disease-targets network was performed under administration of Cytoscape software. Besides, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were administered. H9c2 cells were used to validate the predicted results in cardiomyocytes/reoxygenation model, and anti-inflammatory ability was examined.

Results: A network of a total of 212 nodes and 1016 edges was obtained. Peptide and ubiquitin-like protein ligase binding occupied a leading position of GO enrichment. For KEGG analysis, fluid shear stress and atherosclerosis, as well as inflammation-related pathways were enriched. Cellular validation revealed the anti-inflammatory effect of β-sitosterol, eriodictyol, odoricarpin, and tirucallol as active compounds of TXL.

Conclusion: Our study provided substantial molecular evidence that TXL capsule possessed the characteristics of multitargets with safe profile, and the main component is capable of regulating cytokine level in CHD patients.
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http://dx.doi.org/10.1042/BSR20201349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560518PMC
October 2020

Metformin Is Associated with Higher Incidence of Acidosis, but Not Mortality, in Individuals with COVID-19 and Pre-existing Type 2 Diabetes.

Cell Metab 2020 10 20;32(4):537-547.e3. Epub 2020 Aug 20.

Department of Cardiology, Zhongnan Hospital, School of Basic Medical Science, Wuhan University, Wuhan, China.

The safety and efficacy of anti-diabetic drugs are critical for maximizing the beneficial impacts of well-controlled blood glucose on the prognosis of individuals with COVID-19 and pre-existing type 2 diabetes (T2D). Metformin is the most commonly prescribed first-line medication for T2D, but its impact on the outcomes of individuals with COVID-19 and T2D remains to be clarified. Our current retrospective study in a cohort of 1,213 hospitalized individuals with COVID-19 and pre-existing T2D indicated that metformin use was significantly associated with a higher incidence of acidosis, particularly in cases with severe COVID-19, but not with 28-day COVID-19-related mortality. Furthermore, metformin use was significantly associated with reduced heart failure and inflammation. Our findings provide clinical evidence in support of continuing metformin treatment in individuals with COVID-19 and pre-existing T2D, but acidosis and kidney function should be carefully monitored in individuals with severe COVID-19.
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http://dx.doi.org/10.1016/j.cmet.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439986PMC
October 2020

Hyaluronan promotes the regeneration of vascular smooth muscle with potent contractile function in rapidly biodegradable vascular grafts.

Biomaterials 2020 10 16;257:120226. Epub 2020 Jul 16.

State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), College of Life Sciences, Nankai University, Tianjin, 300071, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China. Electronic address:

The regeneration of smooth muscle with physiological functions has been a key challenge in vascular tissue engineering. Hyaluronan (HA), as a major component of the extracellular matrix, plays a vital role in regulating tissue injury and repair. In this study, a biomimetic vascular graft was prepared by co-electrospinning of synthetic degradable polymers and native ECM components including collagen type-I as well as low and high molecular weight HA (LMW HA and HMW HA). Upon implantation in the rat abdominal aorta, the grafts exhibited sustained HA release that effectively enhanced the regeneration of vascular smooth muscle. Besides, LMW HA loaded vascular grafts demonstrated rapid endothelialization compared to the other groups. More importantly, HA-loaded poly(L-lactide-co-caprolactone) grafts demonstrated an optimal vascular media layer accompanied by well-organized elastin fibers after long-term implantation (6 months), and they maintained potent physiological function up to 1/3 that of the native artery. In contrast, inadequate smooth muscle regeneration was observed in poly(ε-caprolactone) grafts due to slow degradation restricting the regeneration. The mechanism was further investigated and explained by the HA-induced migration of smooth muscle cell (SMC) via CD44-mediated signaling. Besides, low molecular weight HA can promote the migration of vascular progenitor cells that further differentiate into SMCs. These results highlight the importance of HA in the regeneration of functional vascular smooth muscle, and provide a new insight into the fabrication of tissue engineering vascular grafts (TEVGs) via combining rapidly degradable polymers and bioactive ECM components that hold great translational potential.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120226DOI Listing
October 2020

NSun2 regulates aneurysm formation by promoting autotaxin expression and T cell recruitment.

Cell Mol Life Sci 2021 Feb 30;78(4):1709-1727. Epub 2020 Jul 30.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China.

Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell infiltration and aggravated by hyperhomocysteinemia (HHcy). It is unknown whether the homocysteine (Hcy)-activated RNA methyltransferase NOP2/Sun domain family member 2 (NSun2) is associated with AAA. Here, we found that NSun2 deficiency significantly attenuated elastase-induced and HHcy-aggravated murine AAA with decreased T cell infiltration in the vessel walls. T cell labeling and adoptive transfer experiments confirmed that NSun2 deficiency inhibited the chemotaxis of vessels to T cells. RNA sequencing of endothelial cells showed that Hcy induced the accumulation of various metabolic enzymes of the phospholipid PC-LPC-LPA metabolic pathway, especially autotaxin (ATX). In the elastase-induced mouse model of AAA, ATX was specifically expressed in the endothelium and the plasma ATX concentration was upregulated and even higher in the HHcy group, which were decreased dramatically by NSun2 knockdown. In vitro Transwell experiments showed that ATX dose-dependently promoted T cell migration. HHcy may upregulate endothelial ATX expression and secretion and in turn recruit T cells into the vessel walls to induce vascular inflammation and consequently accelerate the pathogenesis of AAA. Mechanistically, secreted ATX interacted with T cells by binding to integrin α4, which subsequently activated downstream FAK/Src-RhoA signaling pathways and then induced T cell chemokinesis and adhesion. ATX overexpression in the vessel walls reversed the inhibited development of AAA in the NSun2-deficient mice. Therefore, NSun2 mediates the development of HHcy-aggravated AAA primarily by increasing endothelial ATX expression, secretion and T cell migration, which is a novel mechanism for HHcy-aggravated vascular inflammation and pathogenesis of AAA.
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http://dx.doi.org/10.1007/s00018-020-03607-7DOI Listing
February 2021

Impact of Local Alloimmunity and Recipient Cells in Transplant Arteriosclerosis.

Circ Res 2020 09 21;127(8):974-993. Epub 2020 Jul 21.

Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (Q. Xiao, Q. Xu).

Rationale: Transplant arteriosclerosis is the major limitation to long-term survival of solid organ transplantation. Although both immune and nonimmune cells have been suggested to contribute to this process, the complex cellular heterogeneity within the grafts, and the underlying mechanisms regulating the disease progression remain largely uncharacterized.

Objective: We aimed to delineate the cellular heterogeneity within the allografts, and to explore possible mechanisms underlying this process.

Methods And Results: Here, we reported the transcriptional profiling of 11 868 cells in a mouse model of transplant arteriosclerosis by single-cell RNA sequencing. Unbiased clustering analyses identified 21 cell clusters at different stages of diseases, and focused analysis revealed several previously unknown subpopulations enriched in the allografts. Interestingly, we found evidence of the local formation of tertiary lymphoid tissues and suggested a possible local modulation of alloimmune responses within the grafts. Intercellular communication analyses uncovered a potential role of several ligands and receptors, including and , in regulating lymphatic endothelial cell-induced early chemotaxis and infiltration of immune cells. In vivo mouse experiments confirmed the therapeutic potential of CCL21 and CXCR3 neutralizing antibodies in transplant arteriosclerosis. Combinational use of genetic lineage tracing and single-cell techniques further indicate the infiltration of host-derived c-Kit stem cells as heterogeneous populations in the allografts. Finally, we compared the immune response between mouse allograft and atherosclerosis models in single-cell RNA-seq analysis. By analyzing susceptibility genes of disease traits, we also identified several cell clusters expressing genes associated with disease risk.

Conclusions: Our study provides a transcriptional and cellular landscape of transplant arteriosclerosis, which could be fundamental to understanding the initiation and progression of this disease. CCL21/CXCR3 was also identified as important regulators of immune response and may serve as potential therapeutic targets in disease treatment.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316470DOI Listing
September 2020

Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19.

Hypertension 2020 10 14;76(4):1104-1112. Epub 2020 Jul 14.

Department of Urology (P.L.), Wuhan Third Hospital and Tongren Hospital of Wuhan University, China.

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] <0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] <0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] <0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] <0.001), and CK was 3.56 ([95% CI, 2.53-5.02] <0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375179PMC
October 2020

Regression of Atherosclerosis in ApoE-/- Mice Via Modulation of Monocyte Recruitment and Phenotype, Induced by Weekly Dosing of a Novel "Cytotopic" Anti-Thrombin Without Prolonged Anticoagulation.

J Am Heart Assoc 2020 07 2;9(13):e014811. Epub 2020 Jul 2.

Department of Inflammation Biology School of Immunology and Microbial Sciences King's College London, Guy's Hospital London United Kingdom.

Background Anticoagulants induce atherosclerosis regression in animal models but exploiting this clinically is limited by bleeding events. Here we test a novel thrombin inhibitor, PTL060, comprising hirulog covalently linked to a synthetic myristoyl electrostatic switch to tether to cell membranes. Methods and Results ApoE-/- mice were fed chow or high-fat diets, before transplantation of congenic aortic segments or injection of PTL060, parental hirulog, control saline, or labeled CD11b positive cells. Aortic transplants from transgenic mice expressing anticoagulants on endothelium did not develop atherosclerosis. A single intravenous injection of PTL060, but not hirulog inhibited atheroma development by >50% compared with controls when assessed 4 weeks later. Mice had prolonged bleeding times for only one seventh of the time that PTL060 was biologically active. Repeated weekly injections of PTL060 but not hirulog caused regression of atheroma. We dissected 2 contributory mechanisms. First, the majority of CCR2+ (C-C chemokine receptor type 2+) monocytes recruited into plaques expressed CCR7 (C-C chemokine receptor type 7), ABCA1 (ATP-binding cassette transporter - 1), and interleukin-10 in PTL060 mice, a phenotype seen in <20% of CCR2+ recruits in controls. Second, after several doses, there was a significant reduction in monocyte recruits, the majority of which were CCR2-negative with a similar regression-associated phenotype. Regression equivalent to that induced by intravenous PTL060 was induced by adoptive transfer of CD11b+ cells pre-coated with PTL060. Conclusions Covalent linkage of a myristoyl electrostatic switch onto hirulog in PTL060 uncouples the pharmacodynamic effects on hemostasis and atherosclerosis, such that plaque regression, mediated predominantly via effects on monocytes, is accompanied by only transient anticoagulation.
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http://dx.doi.org/10.1161/JAHA.119.014811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670518PMC
July 2020

In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19.

Cell Metab 2020 08 24;32(2):176-187.e4. Epub 2020 Jun 24.

Department of Intensive Care Unit, Wuhan Third Hospital & Tongren Hospital of Wuhan University, Wuhan, China.

Statins are lipid-lowering therapeutics with favorable anti-inflammatory profiles and have been proposed as an adjunct therapy for COVID-19. However, statins may increase the risk of SARS-CoV-2 viral entry by inducing ACE2 expression. Here, we performed a retrospective study on 13,981 patients with COVID-19 in Hubei Province, China, among which 1,219 received statins. Based on a mixed-effect Cox model after propensity score-matching, we found that the risk for 28-day all-cause mortality was 5.2% and 9.4% in the matched statin and non-statin groups, respectively, with an adjusted hazard ratio of 0.58. The statin use-associated lower risk of mortality was also observed in the Cox time-varying model and marginal structural model analysis. These results give support for the completion of ongoing prospective studies and randomized controlled trials involving statin treatment for COVID-19, which are needed to further validate the utility of this class of drugs to combat the mortality of this pandemic.
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http://dx.doi.org/10.1016/j.cmet.2020.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311917PMC
August 2020

Single-cell RNA sequencing reveals cell type- and artery type-specific vascular remodelling in male spontaneously hypertensive rats.

Cardiovasc Res 2021 03;117(4):1202-1216

Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, 319 Zhongshan Road, Luzhou 646000, China.

Aims: Hypertension is a major risk factor for cardiovascular diseases. However, vascular remodelling, a hallmark of hypertension, has not been systematically characterized yet. We described systematic vascular remodelling, especially the artery type- and cell type-specific changes, in hypertension using spontaneously hypertensive rats (SHRs).

Methods And Results: Single-cell RNA sequencing was used to depict the cell atlas of mesenteric artery (MA) and aortic artery (AA) from SHRs. More than 20 000 cells were included in the analysis. The number of immune cells more than doubled in aortic aorta in SHRs compared to Wistar Kyoto controls, whereas an expansion of MA mesenchymal stromal cells (MSCs) was observed in SHRs. Comparison of corresponding artery types and cell types identified in integrated datasets unravels dysregulated genes specific for artery types and cell types. Intersection of dysregulated genes with curated gene sets including cytokines, growth factors, extracellular matrix (ECM), receptors, etc. revealed vascular remodelling events involving cell-cell interaction and ECM re-organization. Particularly, AA remodelling encompasses upregulated cytokine genes in smooth muscle cells, endothelial cells, and especially MSCs, whereas in MA, change of genes involving the contractile machinery and downregulation of ECM-related genes were more prominent. Macrophages and T cells within the aorta demonstrated significant dysregulation of cellular interaction with vascular cells.

Conclusion: Our findings provide the first cell landscape of resistant and conductive arteries in hypertensive animal models. Moreover, it also offers a systematic characterization of the dysregulated gene profiles with unbiased, artery type-specific and cell type-specific manners during hypertensive vascular remodelling.
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http://dx.doi.org/10.1093/cvr/cvaa164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983007PMC
March 2021

Patient-level and system-level barriers associated with treatment delays for ST elevation myocardial infarction in China.

Heart 2020 10 24;106(19):1477-1482. Epub 2020 Jun 24.

The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.

Objective: This study aims to understand the current ST elevated myocardial infarction (STEMI) treatment process in Guangdong Province and explore patient-level and system-level barriers associated with delay in STEMI treatment, so as to provide recommendations for improvement.

Methods: This is a qualitative study. Data were collected using semistructured, face-to-face individual interviews from April 2018 to January 2019. Participants included patients with STEMI, cardiologists and nurses from hospitals, emergency department doctors, primary healthcare providers, local health governors, and coordinators at the emergency medical system (EMS). An inductive thematic analysis was adopted to generate overarching themes and subthemes for potential causes of STEMI treatment delay. The WHO framework for people-centred integrated health services was used to frame recommendations for improving the health system.

Results: Thirty-two participants were interviewed. Patient-level barriers included poor knowledge in recognising STEMI symptoms and not calling EMS when symptoms occurred. Limited capacity of health professionals in hospitals below the tertiary level and lack of coordination between hospitals of different levels were identified as the main system-level barriers. Five recommendations were provided: (1) enhance public health education; (2) strengthen primary healthcare workforce; (3) increase EMS capacity; (4) establish an integrated care model; and (5) harness government's responsibilities.

Conclusions: Barriers associated with delay in STEMI treatment were identified at both patient and system levels. The results of this study provide a useful evidence base for future intervention development to improve the quality of STEMI treatment and patient outcomes in China and other countries in a similar situation.
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http://dx.doi.org/10.1136/heartjnl-2020-316621DOI Listing
October 2020

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19.

Circ Res 2020 06 17;126(12):1671-1681. Epub 2020 Apr 17.

General Surgery, Huanggang Central Hospital, Wuhan, China (W.M.).

Rationale: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension.

Objective: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19.

Methods And Results: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; =0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; =0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; =0.01) in patients with COVID-19 and coexisting hypertension.

Conclusions: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265882PMC
June 2020

Single-cell gene profiling and lineage tracing analyses revealed novel mechanisms of endothelial repair by progenitors.

Cell Mol Life Sci 2020 Dec 13;77(24):5299-5320. Epub 2020 Mar 13.

Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.

Stem/progenitor cells (SPCs) have been implicated to participate in vascular repair. However, the exact role of SPCs in endothelial repair of large vessels still remains controversial. This study aimed to delineate the cellular heterogeneity and possible functional role of endogenous vascular SPCs in large vessels. Using single-cell RNA-sequencing (scRNA-seq) and genetic lineage tracing mouse models, we uncovered the cellular heterogeneity of SPCs, i.e., c-Kit cells in the mouse aorta, and found that endogenous c-Kit cells acquire endothelial cell fate in the aorta under both physiological and pathological conditions. While c-Kit cells contribute to aortic endothelial turnover in the atheroprone regions during homeostasis, recipient c-Kit cells of nonbone marrow source replace both luminal and microvessel endothelial cells in transplant arteriosclerosis. Single-cell pseudotime analysis of scRNA-seq data and in vitro cell experiments suggest that vascular SPCs display endothelial differentiation potential and undergo metabolic reprogramming during cell differentiation, in which AKT/mTOR-dependent glycolysis is critical for endothelial gene expression. These findings demonstrate a critical role for c-Kit lineage cells in aortic endothelial turnover and replacement, and may provide insights into therapeutic strategies for vascular diseases.
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http://dx.doi.org/10.1007/s00018-020-03480-4DOI Listing
December 2020
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