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Circulation Mar 2024The adult mammalian heart is incapable of regeneration, whereas a transient regenerative capacity is maintained in the neonatal heart, primarily through the...
BACKGROUND
The adult mammalian heart is incapable of regeneration, whereas a transient regenerative capacity is maintained in the neonatal heart, primarily through the proliferation of preexisting cardiomyocytes. Neonatal heart regeneration after myocardial injury is accompanied by an expansion of cardiac fibroblasts and compositional changes in the extracellular matrix. Whether and how these changes influence cardiomyocyte proliferation and heart regeneration remains to be investigated.
METHODS
We used apical resection and myocardial infarction surgical models in neonatal and adult mice to investigate extracellular matrix components involved in heart regeneration after injury. Single-cell RNA sequencing and liquid chromatography-mass spectrometry analyses were used for versican identification. Cardiac fibroblast-specific deletion was achieved using the mouse strains and . Molecular signaling pathways related to the effects of versican were assessed through Western blot, immunostaining, and quantitative reverse transcription polymerase chain reaction. Cardiac fibrosis and heart function were evaluated by Masson trichrome staining and echocardiography, respectively.
RESULTS
Versican, a cardiac fibroblast-derived extracellular matrix component, was upregulated after neonatal myocardial injury and promoted cardiomyocyte proliferation. Conditional knockout of in cardiac fibroblasts decreased cardiomyocyte proliferation and impaired neonatal heart regeneration. In adult mice, intramyocardial injection of versican after myocardial infarction enhanced cardiomyocyte proliferation, reduced fibrosis, and improved cardiac function. Furthermore, versican augmented the proliferation of human induced pluripotent stem cell-derived cardiomyocytes. Mechanistically, versican activated integrin β1 and downstream signaling molecules, including ERK1/2 and Akt, thereby promoting cardiomyocyte proliferation and cardiac repair.
CONCLUSIONS
Our study identifies versican as a cardiac fibroblast-derived pro-proliferative proteoglycan and clarifies the role of versican in promoting adult cardiac repair. These findings highlight its potential as a therapeutic factor for ischemic heart diseases.
Topics: Animals; Humans; Mice; Animals, Newborn; Cell Proliferation; Heart; Heart Injuries; Induced Pluripotent Stem Cells; Mammals; Myocardial Infarction; Myocytes, Cardiac; Regeneration; Versicans
PubMed: 37886839
DOI: 10.1161/CIRCULATIONAHA.123.066298 -
Circulation Dec 2021Remodeling of the extracellular matrix (ECM) is a hallmark of heart failure (HF). Our previous analysis of the secretome of murine cardiac fibroblasts returned ADAMTS5...
BACKGROUND
Remodeling of the extracellular matrix (ECM) is a hallmark of heart failure (HF). Our previous analysis of the secretome of murine cardiac fibroblasts returned ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) as one of the most abundant proteases. ADAMTS5 cleaves chondroitin sulfate proteoglycans such as versican. The contribution of ADAMTS5 and its substrate versican to HF is unknown.
METHODS
Versican remodeling was assessed in mice lacking the catalytic domain of ADAMTS5 (Adamts5). Proteomics was applied to study ECM remodeling in left ventricular samples from patients with HF, with a particular focus on the effects of common medications used for the treatment of HF.
RESULTS
Versican and versikine, an ADAMTS-specific versican cleavage product, accumulated in patients with ischemic HF. Versikine was also elevated in a porcine model of cardiac ischemia/reperfusion injury and in murine hearts after angiotensin II infusion. In Adamts5 mice, angiotensin II infusion resulted in an aggravated versican build-up and hyaluronic acid disarrangement, accompanied by reduced levels of integrin β1, filamin A, and connexin 43. Echocardiographic assessment of Adamts5 mice revealed a reduced ejection fraction and an impaired global longitudinal strain on angiotensin II infusion. Cardiac hypertrophy and collagen deposition were similar to littermate controls. In a proteomics analysis of a larger cohort of cardiac explants from patients with ischemic HF (n=65), the use of β-blockers was associated with a reduction in ECM deposition, with versican being among the most pronounced changes. Subsequent experiments in cardiac fibroblasts confirmed that β1-adrenergic receptor stimulation increased versican expression. Despite similar clinical characteristics, patients with HF treated with β-blockers had a distinct cardiac ECM profile.
CONCLUSIONS
Our results in animal models and patients suggest that ADAMTS proteases are critical for versican degradation in the heart and that versican accumulation is associated with impaired cardiac function. A comprehensive characterization of the cardiac ECM in patients with ischemic HF revealed that β-blockers may have a previously unrecognized beneficial effect on cardiac chondroitin sulfate proteoglycan content.
Topics: ADAMTS5 Protein; Animals; Extracellular Matrix; Heart Failure; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Proteoglycans; Proteomics
PubMed: 34806902
DOI: 10.1161/CIRCULATIONAHA.121.055732 -
Circulation Research Sep 2023Using proteomics, we aimed to reveal molecular types of human atherosclerotic lesions and study their associations with histology, imaging, and cardiovascular outcomes.
BACKGROUND
Using proteomics, we aimed to reveal molecular types of human atherosclerotic lesions and study their associations with histology, imaging, and cardiovascular outcomes.
METHODS
Two hundred nineteen carotid endarterectomy samples were procured from 120 patients. A sequential protein extraction protocol was employed in conjunction with multiplexed, discovery proteomics. To focus on extracellular proteins, parallel reaction monitoring was employed for targeted proteomics. Proteomic signatures were integrated with bulk, single-cell, and spatial RNA-sequencing data, and validated in 200 patients from the Athero-Express Biobank study.
RESULTS
This extensive proteomics analysis identified plaque inflammation and calcification signatures, which were inversely correlated and validated using targeted proteomics. The inflammation signature was characterized by the presence of neutrophil-derived proteins, such as S100A8/9 (calprotectin) and myeloperoxidase, whereas the calcification signature included fetuin-A, osteopontin, and gamma-carboxylated proteins. The proteomics data also revealed sex differences in atherosclerosis, with large-aggregating proteoglycans versican and aggrecan being more abundant in females and exhibiting an inverse correlation with estradiol levels. The integration of RNA-sequencing data attributed the inflammation signature predominantly to neutrophils and macrophages, and the calcification and sex signatures to smooth muscle cells, except for certain plasma proteins that were not expressed but retained in plaques, such as fetuin-A. Dimensionality reduction and machine learning techniques were applied to identify 4 distinct plaque phenotypes based on proteomics data. A protein signature of 4 key proteins (calponin, protein C, serpin H1, and versican) predicted future cardiovascular mortality with an area under the curve of 75% and 67.5% in the discovery and validation cohort, respectively, surpassing the prognostic performance of imaging and histology.
CONCLUSIONS
Plaque proteomics redefined clinically relevant patient groups with distinct outcomes, identifying subgroups of male and female patients with elevated risk of future cardiovascular events.
Topics: Female; Humans; Male; Proteomics; Sex Characteristics; Versicans; alpha-2-HS-Glycoprotein; Atherosclerosis; Calcinosis
PubMed: 37646165
DOI: 10.1161/CIRCRESAHA.123.322590 -
International Journal of Molecular... Mar 2023Androgenic alopecia (AGA) is the most common type of hair loss, where local high concentrations of dihydrotestosterone (DHT) in the scalp cause progressive shrinkage of...
Adipose Mesenchymal Stromal Cell-Derived Exosomes Carrying MiR-122-5p Antagonize the Inhibitory Effect of Dihydrotestosterone on Hair Follicles by Targeting the TGF-β1/SMAD3 Signaling Pathway.
Androgenic alopecia (AGA) is the most common type of hair loss, where local high concentrations of dihydrotestosterone (DHT) in the scalp cause progressive shrinkage of the hair follicles, eventually contributing to hair loss. Due to the limitations of existing methods to treat AGA, the use of multi-origin mesenchymal stromal cell-derived exosomes has been proposed. However, the functions and mechanisms of action of exosomes secreted by adipose mesenchymal stromal cells (ADSCs-Exos) in AGA are still unclear. Using Cell Counting Kit-8 (CCK8) analysis, immunofluorescence staining, scratch assays, and Western blotting, it was found that ADSC-Exos contributed to the proliferation, migration, and differentiation of dermal papilla cells (DPCs) and up-regulated the expression of cyclin, β-catenin, versican, and BMP2. ADSC-Exos also mitigated the inhibitory effects of DHT on DPCs and down-regulated transforming growth factor-beta1 (TGF-β1) and its downstream genes. Moreover, high-throughput miRNA sequencing and bioinformatics analysis identified 225 genes that were co-expressed in ADSC-Exos; of these, miR-122-5p was highly enriched and was found by luciferase assays to target SMAD3. ADSC-Exos carrying miR-122-5p antagonized DHT inhibition of hair follicles, up-regulated the expression of β-catenin and versican in vivo and in vitro, restored hair bulb size and dermal thickness, and promoted the normal growth of hair follicles. So, ADSC-Exos enhanced the regeneration of hair follicles in AGA through the action of miR-122-5p and the inhibition of the TGF-β/SMAD3 axis. These results suggest a novel treatment option for the treatment of AGA.
Topics: Humans; Hair Follicle; Transforming Growth Factor beta1; Dihydrotestosterone; beta Catenin; Exosomes; Versicans; Mesenchymal Stem Cells; Signal Transduction; MicroRNAs; Alopecia; Smad3 Protein
PubMed: 36982775
DOI: 10.3390/ijms24065703 -
Advances in Experimental Medicine and... 2020Versican is an extracellular matrix proteoglycan with nonredundant roles in diverse biological and cellular processes, ranging from embryonic development to adult... (Review)
Review
Versican is an extracellular matrix proteoglycan with nonredundant roles in diverse biological and cellular processes, ranging from embryonic development to adult inflammation and cancer. Versican is essential for cardiovascular morphogenesis, neural crest migration, and skeletal development during embryogenesis. In the adult, versican acts as an inflammation "amplifier" and regulator of immune cell activation and cytokine production. Increased versican expression has been observed in a wide range of malignant tumors and has been associated with poor patient outcomes. The main sources of versican production in the tumor microenvironment include accessory cells (myeloid cells and stromal components) and, in some contexts, the tumor cells themselves. Versican has been implicated in several classical hallmarks of cancer such as proliferative signaling, evasion of growth suppressor signaling, resistance to cell death, angiogenesis, and tissue invasion and metastasis. More recently, versican has been implicated in escape from tumor immune surveillance, e.g., through dendritic cell dysfunction. Versican's multiple contributions to benign and malignant biological processes are further diversified through the generation of versican-derived bioactive proteolytic fragments (matrikines), with versikine being the most studied to date. Versican and versican-derived matrikines hold promise as targets in the management of inflammatory and malignant conditions as well as in the development of novel predictive and prognostic biomarkers.
Topics: Extracellular Matrix; Humans; Neoplasms; Tumor Microenvironment; Versicans
PubMed: 32845502
DOI: 10.1007/978-3-030-48457-6_4 -
Respiratory Research May 2023This study aimed to investigate the expression of plasma versican and plasma exosomal versican in non-small cell lung cancer (NSCLC) and its correlation with...
BACKGROUND AND AIMS
This study aimed to investigate the expression of plasma versican and plasma exosomal versican in non-small cell lung cancer (NSCLC) and its correlation with clinicopathological features, and to evaluate its diagnostic performance in NSCLC and its predictive function for NSCLC incidence and metastasis risk.
MATERIALS AND METHODS
There were 110 instances of NSCLC, 42 cases of benign lung disease, and 55 healthy controls from September 2018 to October 2020 at Tongji Hospital Affiliated to Tongji University. Blood was collected and plasma was separated before surgery, and plasma exosomes were extracted by ExoQuick kit. Morphological and molecular phenotype identification of exosomes was performed by transmission electron microscopy, Nanosight particle tracking analysis, and western blotting. Plasma versican and plasma exosomal versican were detected in all subjects to assess their expression levels and diagnostic value in NSCLC. Clinicopathological data were collected to explore correlations between abnormal plasma versican and plasma exosomal versican expression and clinicopathological parameters. Receiver operating characteristic (ROC) curve was used to judge its diagnostic performance in NSCLC, and binary logistic regression analysis was used to predict the risk of NSCLC incidence and metastasis.
RESULTS
Plasma versican and plasma exosomal versican expression in NSCLC patients was significantly upregulated and was significantly higher in T3 + T4 patients compared with T1 + T2 patients (P < 0.05); the levels of plasma versican and plasma exosomal versican were positively correlated with lymph node metastasis, distant metastases (e.g., brain, bone), and mutation(e.g., EGFR,ALK)in NSCLC patients (all P < 0.05). Furthermore, ROC curve analysis showed that plasma versican and plasma exosomal versican had higher AUC values than NSE, CYFRA21-1, and SCC, and better diagnostic performance in NSCLC patients. However, the AUC and diagnostic performances of plasma versican and plasma exosomal versican in advanced-stage NSCLC patients were not shown to be significantly better than CEA. The results of binary logistic regression analysis showed that high levels of plasma exosomal versican had higher predictive value for lung cancer incidence, while high levels of plasma versican had higher predictive value for lung cancer metastasis.
CONCLUSION
Our findings showed that plasma versican and plasma exosomal versican might be potential diagnostic markers for NSCLC. High plasma exosomal versican expression can be used as a predictor of NSCLC risk and high plasma versican expression can be used as a predictor of NSCLC metastasis risk.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Versicans; Biomarkers, Tumor
PubMed: 37259101
DOI: 10.1186/s12931-023-02423-4 -
Open Biology Dec 2020The a disintegrin-like and metalloproteinase with thrombospondin motif (ADAMTS) family comprises 19 proteases that regulate the structure and function of extracellular... (Review)
Review
The a disintegrin-like and metalloproteinase with thrombospondin motif (ADAMTS) family comprises 19 proteases that regulate the structure and function of extracellular proteins in the extracellular matrix and blood. The best characterized cardiovascular role is that of ADAMTS-13 in blood. Moderately low ADAMTS-13 levels increase the risk of ischeamic stroke and very low levels (less than 10%) can cause thrombotic thrombocytopenic purpura (TTP). Recombinant ADAMTS-13 is currently in clinical trials for treatment of TTP. Recently, new cardiovascular roles for ADAMTS proteases have been discovered. Several ADAMTS family members are important in the development of blood vessels and the heart, especially the valves. A number of studies have also investigated the potential role of ADAMTS-1, -4 and -5 in cardiovascular disease. They cleave proteoglycans such as versican, which represent major structural components of the arteries. ADAMTS-7 and -8 are attracting considerable interest owing to their implication in atherosclerosis and pulmonary arterial hypertension, respectively. Mutations in the gene cause progressive heart valve disease and missense variants in are associated with cardiac conduction. In this review, we discuss in detail the evidence for these and other cardiovascular roles of ADAMTS family members, their proteolytic substrates and the potential molecular mechanisms involved.
Topics: ADAMTS Proteins; Animals; Biomarkers; Blood Coagulation; Blood Coagulation Disorders; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Cardiovascular System; Disease Management; Disease Susceptibility; Gene Expression Regulation; Humans; Molecular Targeted Therapy; Multigene Family; Proteoglycans; Proteolysis
PubMed: 33352066
DOI: 10.1098/rsob.200333 -
Glycobiology May 2020Versican (VCAN) proteolysis and the accumulation of VCAN fragments occur in many developmental and disease processes, affecting extracellular matrix (ECM) structure and... (Review)
Review
Versican (VCAN) proteolysis and the accumulation of VCAN fragments occur in many developmental and disease processes, affecting extracellular matrix (ECM) structure and cell phenotype. Little is known about the significance of proteolysis and the roles of fragments, or how this ECM remodeling affects the microenvironment and phenotype of diseased cells. G1-DPEAAE fragments promote aspects of epithelial-mesenchymal transitioning in developing and diseased cells, resulting in cell migration. Enhanced proliferation and invasion of tumor and endothelial cells is directly associated with G1 domain deposition and G1-DPEAAE localization respectively. These tumorigenic and angiogenic roles could explain the disease exacerbating effect often associated with G1-containing fragments, however, the pathogenicity of G1 fragments depends entirely upon the context. Overall, VCAN fragments promote tumorigenesis and inflammation; however, the specific cleavage site, the extent of cleavage activity and the microenvironment in which cleavage occurs collectively determine how this pleiotropic molecule and its fragments influence cells.
Topics: Animals; Epithelial-Mesenchymal Transition; Extracellular Matrix; Humans; Inflammation; Neoplasms; Proteolysis; Versicans
PubMed: 31651027
DOI: 10.1093/glycob/cwz090 -
Methods in Molecular Biology (Clifton,... 2022Versican is a widely distributed chondroitin sulfate proteoglycan that forms large complexes with the glycosaminoglycan hyaluronan (HA). As a consequence of HA binding...
Versican is a widely distributed chondroitin sulfate proteoglycan that forms large complexes with the glycosaminoglycan hyaluronan (HA). As a consequence of HA binding to its receptor CD44 and interactions of the versican C-terminal globular (G3) domain with a variety of extracellular matrix proteins, versican is a key component of well-defined networks in pericellular matrix and extracellular matrix. Versican is crucial for several developmental processes in the embryo ranging from cardiac development to digit separation, and there is an increasing interest in its roles in cancer and inflammation. Versican proteolysis by ADAMTS proteases is highly regulated, occurs at specific peptide bonds, and is relevant to several physiological and disease mechanisms. In this chapter, methods are described for the isolation and detection of intact and cleaved versican in tissues using morphologic and biochemical techniques. These, together with the methodologies for purification and analysis of recombinant versican and an N-terminal versican fragment named versikine that are provided here, are likely to facilitate further progress on the biology of versican and its proteolysis.
Topics: ADAMTS Proteins; Chondroitin Sulfate Proteoglycans; Extracellular Matrix; Hyaluronic Acid; Lectins, C-Type; Proteolysis; Versicans
PubMed: 34626407
DOI: 10.1007/978-1-0716-1398-6_43