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BACKGROUND: Candida albicans is an opportunistic pathogenic yeast, which could become pathogenic in various stressful environmental factors including the spaceflight environment. In this study, we aim to explore the phenotypic changes and possible mechanisms of C. albicans after exposure to spaceflight conditions. RESULTS: The effect of C. albicans after carried on the "SJ-10" satellite for 12 days was evaluated by proliferation, morphology, environmental resistance and virulence experiment. The result showed that the proliferation rate, biofilm formation, antioxidant capacity, cytotoxicity and filamentous morphology of C. albicans were increased in the spaceflight group compared to the control group. Proteomics and metabolomics technologies were used to analyze the profiles of proteins and metabolites in C. albicans under spaceflight conditions. Proteomic analysis identified 548 up-regulated proteins involved in the ribosome, DNA replication, base excision repair and sulfur metabolism in the spaceflight group. Moreover, 332 down-regulated proteins related to metabolic processes were observed. The metabolomic analysis found five differentially expressed metabolites. The combined analysis of proteomic and metabolomic revealed the accumulation of cysteine and methionine in C. albicans after spaceflight. CONCLUSIONS: Mechanisms that could explain the results in the phenotypic experiment of C. albicans were found through proteomic and metabolomic analysis. And our data provide an important basis for the assessment of the risk that C. albicans could cause under spaceflight environment.
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Candida albicans/metabolismo , Metaboloma , Proteoma , Voo Espacial , Candida albicans/citologia , Candida albicans/patogenicidade , Candida albicans/fisiologia , Metabolômica , Proteômica , VirulênciaRESUMO
OBJECTIVE: Cathepsin S (CatS) participates in atherogenesis through several putative mechanisms. The ability of cathepsins to modify histone tail is likely to contribute to stem cell development. Histone deacetylase 6 (HDAC6) is required in modulating the proliferation and migration of various types of cancer cells. Here, we investigated the cross talk between CatS and HADC6 in injury-related vascular repair in mice. APPROACH AND RESULTS: Ligation injury to the carotid artery in mice increased the CatS expression, and CatS-deficient mice showed reduced neointimal formation in injured arteries. CatS deficiency decreased the phosphorylation levels of p38 mitogen-activated protein kinase, Akt, and HDAC6 and toll-like receptor 2 expression in ligated arteries. The genetic or pharmacological inhibition of CatS also alleviated the increased phosphorylation of p38 mitogen-activated protein kinase, Akt, and HDAC6 induced by platelet-derived growth factor BB in cultured vascular smooth muscle cells (VSMCs), and p38 mitogen-activated protein kinase inhibition and Akt inhibition decreased the phospho-HDAC6 levels. Moreover, CatS inhibition caused decrease in the levels of the HDAC6 activity in VSMCs in response to platelet-derived growth factor BB. The HDAC6 inhibitor tubastatin A downregulated platelet-derived growth factor-induced VSMC proliferation and migration, whereas HDAC6 overexpression exerted the opposite effect. Tubastatin A also decreased the intimal VSMC proliferation and neointimal hyperplasia in response to injury. Toll-like receptor 2 silencing decreased the phosphorylation levels of p38 mitogen-activated protein kinase, Akt, and HDAC6 and VSMC migration and proliferation. CONCLUSIONS: This is the first report detailing cross-interaction between toll-like receptor 2-mediated CatS and HDAC6 during injury-related vascular repair. These data suggest that CatS/HDAC6 could be a potential therapeutic target for the control of vascular diseases that are involved in neointimal lesion formation.
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Lesões das Artérias Carótidas/enzimologia , Artéria Carótida Primitiva/enzimologia , Catepsinas/metabolismo , Histona Desacetilases/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor 2 Toll-Like/metabolismo , Cicatrização , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/patologia , Artéria Carótida Primitiva/efeitos dos fármacos , Artéria Carótida Primitiva/patologia , Catepsinas/antagonistas & inibidores , Catepsinas/deficiência , Catepsinas/genética , Pontos de Checagem do Ciclo Celular , Movimento Celular , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Genótipo , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Masculino , Camundongos Knockout , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Neointima , Fenótipo , Fosforilação , Inibidores de Proteases/farmacologia , Interferência de RNA , Transdução de Sinais , Receptor 2 Toll-Like/genética , Transfecção , Remodelação Vascular , Cicatrização/efeitos dos fármacosRESUMO
OBJECTIVE: This study aimed to examine the changes in serum Low Density Lipoprotein Cholesterol (LDL-C) and Soluble Growth Stimulating Expressed Gene 2 Protein (sST2) among Heart Failure (HF) patients with varying ejection fractions and their clinical significance, providing a reference for the clinical assessment of HF severity. METHODS: A total of 238 HF patients treated in our hospital's cardiology department from September 2019 to December 2021 were selected; 68 patients hospitalized in the same period were selected as the control group. General information, LDL-C and echocardiographic results of admitted patients were collected. According to LVEF results and the latest European Society of Cardiology standards in 2021, HF patients were categorized into those with HFpEF (nâ =â 95), HFmrEF (nâ =â 60), and HFrEF (nâ =â 83). Meanwhile, venous blood was collected to determine sST2 and NT-proBNP to compare and analyze the changes and clinical significance of sST2 and LDL-C across the groups. RESULTS: Compared to the control group, the HF group showed significant differences in age, gender, heart rate, smoking history, history of atrial fibrillation, history of diabetes, LVEDD, LVEF, sST2, and NT-proBNP levels (Pâ <â .05), but not in LDL-C levels. Significant differences (Pâ <â .05) were also found among the 3 HF groups in terms of age, gender, history of atrial fibrillation, LVEDD, LVEF, LDL-C, sST2, and NT-proBNP levels, with an increase in LVEDD, LDL-C, sST2, and NT-proBNP values as the ejection fraction decreased. ROC curve analysis indicated that the area under the curve (AUC) for sST2 in diagnosing HF was 0.915 (Pâ <â .05), with an optimal cutoff value of 23.71 ng/mL, a sensitivity of 76.5%, and a specificity of 95.6%; LDL-C was not a significant diagnostic marker for HF (Pâ >â .05). Coronary artery disease, NT-proBNP, and sST2 were identified as risk factors for HF. With each unit increase in coronary artery disease, the risk of HF increased by 36.3%; for NT-proBNP, the risk increased by 1.3% per unit; and for sST2, it increased by 18.3% per unit. CONCLUSION: As the ejection fraction decreases in HF patients, serum sST2 and LDL-C values progressively increase, which is clinically significant for predicting the severity of HF. sST2 is an independent risk factor for HF and can enhance the diagnostic accuracy for HF.
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Fibrilação Atrial , Doença da Artéria Coronariana , Insuficiência Cardíaca , Humanos , Biomarcadores , Prognóstico , Volume Sistólico , Relevância Clínica , LDL-Colesterol , Peptídeo Natriurético Encefálico , Fragmentos de PeptídeosRESUMO
The patient's vasospastic variant angina manifested as syncope with asymptomatic ischemic episodes, and repeated 24-h dynamic electrocardiogram and coronary angiography examinations combined with coronary provocation spasm tests were necessary for its diagnosis and management.
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Microbial safety has become a research hotspot with the development of manned space technology. Escherichia coli is a conditional pathogen that can cause infectious diseases. Therefore, it is necessary to study the influence of the space environment on E. coli. Phenotypic experiments including growth curves, morphology, and environmental resistance experiment were used to study the phenotypic changes of E. coli after exposure to the space environment for 12 days carried by the "SJ-10" satellite. Tandem mass tag was used to assess the proteome change of E. coli. We found that the survival rate of E. coli in the spaceflight group was decreased when cultivated in acidic and high-salt environments. Proteomic analysis identified 72 downregulated proteins involved in chemotaxis, intracellular pH elevation, glycolate catabolic process, and glutamate metabolic process in the spaceflight group. Meanwhile, only one protein mtr that was involved in the uptake of tryptophan in E. coli was upregulated in the spaceflight group. Our research showed that proteomics results can explain phenotypic results, which demonstrated the successful application of proteomics in mechanism research. Our data provide a comprehensive resource for understanding the effect of the space environment on E. coli.
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Background Although apoptosis and cell proliferation have been extensively investigated in atherosclerosis and restenosis postinjury, the communication between these 2 cellular events has not been evaluated. Here, we report an inextricable communicative link between apoptosis and smooth muscle cell proliferation in the promotion of vascular remodeling postinjury. Methods and Results Cathepsin K-mediated caspase-8 maturation is a key initial step for oxidative stress-induced smooth muscle cell apoptosis. Apoptotic cells generate a potential growth-stimulating signal to facilitate cellular mass changes in response to injury. One downstream mediator that cathepsin K regulates is PLF-1 (proliferin-1), which can potently stimulate growth of surviving neighboring smooth muscle cells through activation of PI3K/Akt/p38MAPK (phosphatidylinositol 3-kinase/protein kinase B/p38 mitogen-activated protein kinase)-dependent and -independent mTOR (mammalian target of rapamycin) signaling cascades. We observed that cathepsin K deficiency substantially mitigated neointimal hyperplasia by reduction of Toll-like receptor-2/caspase-8-mediated PLF-1 expression. Interestingly, PLF-1 blocking, with its neutralizing antibody, suppressed neointima formation and remodeling in response to injury in wild-type mice. Contrarily, administration of recombinant mouse PLF-1 accelerated injury-induced vascular actions. Conclusions This is the first study detailing PLF-1 as a communicator between apoptosis and proliferation during injury-related vascular remodeling and neointimal hyperplasia. These data suggested that apoptosis-driven expression of PLF-1 is thus a novel target for treatment of apoptosis-based hyperproliferative disorders.
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Apoptose/fisiologia , Proliferação de Células/fisiologia , Miócitos de Músculo Liso/fisiologia , Prolactina/fisiologia , Túnica Íntima/patologia , Animais , Hiperplasia , Masculino , Camundongos , Ratos , Remodelação Vascular/fisiologiaRESUMO
BACKGROUND: Cathepsin K (CatK) is a widely expressed cysteine protease that has gained attention because of its enzymatic and non-enzymatic functions in signalling. Here, we examined whether CatK-deficiency (CatK-/- ) would mitigate injury-related skeletal muscle remodelling and fibrosis in mice, with a special focus on inflammation and muscle cell apoptosis. METHODS: Cardiotoxin (CTX, 20 µM/200 µL) was injected into the left gastrocnemius muscle of male wild-type (CatK+/+ ) and CatK-/- mice, and the mice were processed for morphological and biochemical studies. RESULTS: On post-injection Day 14, CatK deletion ameliorated muscle interstitial fibrosis and remodelling and performance. At an early time point (Day 3), CatK-/- reduced the lesion macrophage and leucocyte contents and cell apoptosis, the mRNA levels of monocyte chemoattractant protein-1, toll-like receptor-2 and toll-like receptor-4, and the gelatinolytic activity related to matrix metalloproteinase-2/-9. CatK deletion also restored the protein levels of caspase-3 and cleaved caspase-8 and the ratio of the BAX to the Bcl-2. Moreover, CatK deficiency protected muscle fibre laminin and desmin disorder in response to CTX injury. These beneficial muscle effects were mimicked by CatK-specific inhibitor treatment. In vitro experiments demonstrated that pharmacological CatK inhibition reduced the apoptosis of C2C12 mouse myoblasts and the levels of BAX and caspase-3 proteins induced by CTX. CONCLUSIONS: These results demonstrate that CatK plays an essential role in skeletal muscle loss and fibrosis in response to CTX injury, possibly via a reduction of inflammation and cell apoptosis, suggesting a novel therapeutic strategy for the control of skeletal muscle diseases by regulating CatK activity.
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Cardiotoxinas/metabolismo , Catepsina K/metabolismo , Músculo Esquelético/metabolismo , Animais , Apoptose , Masculino , CamundongosRESUMO
BACKGROUND: The mechanism by which angiogenesis declines with aging remains largely unknown. Given that the plasma levels of adiponectin (APN) are decreased in the presence of ischemic cardiovascular disease, we explore the possible mechanisms by which APN/adiponectin receptor1 (AdipoR1) axis inactivation contributes to the decline in vascular regeneration capacity in elderly animals. METHODS AND RESULTS: To study aging-related changes in the APN/AdipoR1 axis and its impact on ischemia-induced angiogenesis, a hindlimb ischemia model was applied to young and aged mice. Aging impaired ischemia-induced blood flow recovery. An ELISA showed that the aged mice had decreased plasma APN levels. Immunostaining showed lesser capillary formation in the aged mice. The aged ischemic muscles had decreased levels of AdipoR1, peroxisome proliferator activated receptor-γ (PPAR-γ), PPAR-γ co-activator 1α (PGC-1α), phospho-AMP-activated protein kinase α (p-AMPK-α), and B cell lymphoma-2 (Bcl-2) and increased levels of cleaved caspase-8 (C-caspase-8) and gp91phox/p22phox genes or/and proteins, nicotinamide adenine dinucleotide phosphate oxidase activity, superoxide production, and matrix metalloproteinase-2/-9 activity as well as increased numbers of infiltrated macrophages and leucocytes. In in vitro experiments, aged endothelial cells had negative changes in the levels of PPAR-γ, PGC-1α, p-AMPK-α, Bcl-2, and C-caspase-8 proteins in response to oxidative stress. Genetic interventions targeted toward APN and AdipoR1 negatively affected the targeted angiogenic protein levels in aged muscles and angiogenic actions and/or aged endothelial events. CONCLUSION: These findings indicate that aging can reduce angiogenesis in response to hypoxia via an impaired APN-AdipoR1-dependent mechanism that may be mediated by PPAR-γ/PGC-1α signaling inactivation in advanced age.
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Adiponectina/metabolismo , Envelhecimento/metabolismo , Neovascularização Patológica/metabolismo , Receptores de Adiponectina/metabolismo , Animais , Modelos Animais de Doenças , Hipóxia/metabolismo , Isquemia/complicações , Camundongos , Neovascularização Patológica/etiologia , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de SinaisRESUMO
The mechanism by which angiogenesis declines with aging is not fully understood. Soluble vascular endothelial growth factor receptor 1 (VEGFR1) form (sFlt1) contributes to endothelial dysfunction in pathological conditions. However, the roles of sFlt1 in ischemia-induced neovascularizationof aged animals have not been investigated. To study aging-related sFlt1 change and its impact on ischemia-induced neovascularization, a hindlimb ischemia model was applied to young and aged mice. Blood flow imaging assay revealed that the blood flow recovery remained impaired throughout the follow-up period. At day 14, immunostaining showed lesser capillary formation in the aged mice. An ELISA showed that the aged mice had increased plasma sFlt-1 levels at indicated time points after surgery. On operative day 4, the aged ischemic muscles had decreased levels of p-VEGFR2 and p-Akt and increased levels of sFlt-1, Wnt5a, and SC35 genes or/and protein as well as increased numbers of inflammatory cells (macrophages and leucocytes) and matrix metalloproteinase-9 activity. Immnunofluorescence showed that Flt-1 was co-localized with CD11b+ macrophages of aged ischemic muscles. Hypoxia stimulated sFlt1 expression in CD11b+ cells of aged bone-marrow (BM), and this effect was diminished by siWnt5a. The cultured medium of aged mice BM-derived CD11b+ cells suppressed human endothelial cell (EC) and endothelial progenitor cell (EPC) angiogenic actions induced by VEGF, and these decreases were improved by treatment with siWnt5a-conditioned medium. Thus, aging appears to decline neovascularization in response to ischemic stress via the VEGFR2/Akt signaling inactivation in ECs and ECPs that is mediated by Wnt5a/SC35 axis activated macrophages-derived sFlt1 production in advanced age.
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BACKGROUND: Adipose-derived adipokines have been demonstrated to be associated with the development of experimental heart disease through chronic inflammation and cardiac cell apoptosis. Omentin is to be one of the novel adipokines. The aim of this study is to investigate the relationship between circulating omentin and cardiac dysfunction in patients with chronic heart failure (CHF). METHODS: A total of 189 CHF patients were studied, determining serum omentin and echocardiographic parameters. All participants were divided into two experimental groups: the 111 patients who had a left ventricular ejection fraction (EF) ≥40% (EF-H) and the 78 patients exhibiting EF values <40% (EF-L). RESULTS: The EF-L group showed significantly higher circulating omentin levels compared to the EF-H group (210.8±67.2 vs. 155.3±45.3, P<0.001; Student's t-test). Overall, the data of the linear regression analysis revealed that serum omentin levels correlated positively with left atrial diameters (r=0.31, P=0.006), left ventricular end-systolic dimensions (r=0.42, P<0.001), and left ventricular end-diastolic dimensions (r=0.38, P=0.002) and negatively with left ventricular EF (r=-0.45, P=0.001; Spearmen's rank correlations coefficients for each). The multiple regression model included all variables at p<0.1 by the univariate analysis. A multiple logistic regression analysis demonstrated that high levels of patients' serum omentin were associated with cardiac dysfunction in patients with CHF (OR=1.22; 95% CI: 0.91-1.58; P=0.009). CONCLUSIONS: These findings suggested that elevated serum omentin levels were only very mildly related to the changes in cardiac volume and function in CHF patients. Further studies are then needed to assess the real clinical value of omentin in this setting.
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Citocinas/sangue , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/metabolismo , Lectinas/sangue , Idoso , Biomarcadores , Doença Crônica , Ecocardiografia , Feminino , Proteínas Ligadas por GPI/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
BACKGROUND AND AIMS: Exposure to psychosocial stress is a risk factor for cardiovascular disorders. Because the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonist prevents cardiovascular injury, we investigated the beneficial effects and mechanism of the GLP-1 analogue exenatide on stress-related vascular senescence and atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat (HF) diet. METHODS: ApoE-/- mice fed the HF diet were assigned to non-stressed and immobilized-stress groups for 12 weeks. Mice fed the HF diet were divided into 2 groups and administered vehicle or exenatide for 12 weeks under stress conditions. RESULTS: Chronic stress enhanced vascular endothelial senescence and atherosclerotic plaque growth. The stress increased the levels of plasma depeptidyl peptidase-4 activity and decreased the levels of plasma GLP-1 and both plasma and adipose adiponectin (APN). As compared with the mice subjected to stress alone, the exenatide-treated mice had decreased plaque microvessel density, macrophage accumulation, broken elastin, and enhanced plaque collagen volume, and lowered levels of peroxisome proliferator-activated receptor-α, gp91phox osteopontin, C-X-C chemokine receptor-4, toll-like receptor-2 (TLR2), TLR4, and cathepsins K, L, and S mRNAs and/or proteins. Exenatide reduced aortic matrix metalloproteinase-9 (MMP-9) and MMP-2 gene expression and activities. Exenatide also stimulated APN expression of preadipocytes and inhibited ox-low density lipoprotein-induced foam cell formation of monocytes in stressed mice. CONCLUSIONS: These results indicate that the exenatide-mediated beneficial vascular actions are likely attributable, at least in part, to the enhancement of APN production and the attenuation of plaque oxidative stress, inflammation, and proteolysis in ApoE-/- mice under chronic stress.
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Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Senescência Celular/efeitos dos fármacos , Dieta Hiperlipídica , Incretinas/farmacologia , Peptídeos/farmacologia , Placa Aterosclerótica , Estresse Psicológico/complicações , Peçonhas/farmacologia , Adiponectina/sangue , Fatores Etários , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Doença Crônica , Dipeptidil Peptidase 4/sangue , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Exenatida , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Células Espumosas/patologia , Predisposição Genética para Doença , Peptídeo 1 Semelhante ao Glucagon/sangue , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Mediadores da Inflamação/sangue , Masculino , Camundongos Knockout para ApoE , Estresse Oxidativo/efeitos dos fármacos , Peptídeo Hidrolases/metabolismo , Fenótipo , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVES: Exposure to psychosocial stress is a risk factor for cardiovascular disease. Given that dipeptidyl peptidase-4 (DPP4) regulates several intracellular signaling pathways associated with glucagon-like peptide-1 (GLP-1) metabolism, we investigated the role of DPP4 in stress-related vascular senescence and atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. METHODS AND RESULTS: ApoE-/- mice fed a high-fat (HF) diet were randomly assigned to one of non-stress and immobilized stress groups for 12weeks. Chronic stress accelerated vascular senescence and atherosclerotic plaque growth at the aortic roots. Stressed mice had increased levels of plasma DPP4 and decreased levels of plasma GLP-1 and adiponectin (APN) and adipose APN expression. Stress increased plaque macrophage infiltration, neovessel density, and elastin fragmentation, lessened the plaque collagen content, and increased the levels of toll-like receptor-2 (TLR2), TLR4, C-X-C chemokine receptor-4, cathepsins S and K, osteopontin, peroxisome proliferator-activated receptor-α, p16INK4A, p21, and gp91phox mRNAs and/or proteins. Stressed aortas had also increased matrix metalloproteinase-2 (MMP-2) and MMP-9 activities. DPP4 inhibition with anagliptin reversed stress-related atherosclerotic lesion formation, and this benefit was abrogated by APN blocking. In vitro, the GLP-1 receptor agonist exenatide stimulated APN expression in 3T3-L1 cells. CONCLUSIONS: These results indicate that the DPP4 inhibition-mediated benefits are likely attributable, at least in part, to attenuation of plaque inflammation, oxidative stress and proteolysis associated with GLP-1-mediated APN production in ApoE-/- mice under stress. Thus, DPP4 will be a novel therapeutic target for the treatment of stress-related cardiovascular disease.
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Envelhecimento/metabolismo , Apolipoproteínas E/deficiência , Aterosclerose/sangue , Dieta Hiperlipídica/efeitos adversos , Dipeptidil Peptidase 4/sangue , Estresse Psicológico/sangue , Células 3T3-L1 , Envelhecimento/psicologia , Animais , Aterosclerose/patologia , Aterosclerose/psicologia , Biomarcadores/sangue , Doença Crônica , Dipeptidil Peptidase 4/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Distribuição Aleatória , Estresse Psicológico/patologia , Estresse Psicológico/psicologiaRESUMO
BACKGROUND: Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular aging and regeneration. Given that dipeptidyl peptidase-4 (DPP4) regulates several intracellular signaling pathways associated with the glucagon-like peptide-1 (GLP-1) metabolism, we investigated the role of DPP4/GLP-1 axis in vascular senescence and ischemia-induced neovascularization in mice under chronic stress, with a special focus on adiponectin -mediated peroxisome proliferator activated receptor-γ/its co-activator 1α (PGC-1α) activation. METHODS AND RESULTS: Seven-week-old mice subjected to restraint stress for 4 weeks underwent ischemic surgery and were kept under immobilization stress conditions. Mice that underwent ischemic surgery alone served as controls. We demonstrated that stress impaired the recovery of the ischemic/normal blood-flow ratio throughout the follow-up period and capillary formation. On postoperative day 4, stressed mice showed the following: increased levels of plasma and ischemic muscle DPP4 and decreased levels of GLP-1 and adiponectin in plasma and phospho-AMP-activated protein kinase α (p-AMPKα), vascular endothelial growth factor, peroxisome proliferator activated receptor-γ, PGC-1α, and Sirt1 proteins and insulin receptor 1 and glucose transporter 4 genes in the ischemic tissues, vessels, and/or adipose tissues and numbers of circulating endothelial CD31+/c-Kit+ progenitor cells. Chronic stress accelerated aortic senescence and impaired aortic endothelial sprouting. DPP4 inhibition and GLP-1 receptor activation improved these changes; these benefits were abrogated by adiponectin blocking and genetic depletion. CONCLUSIONS: These results indicate that the DPP4/GLP-1-adiponectin axis is a novel therapeutic target for the treatment of vascular aging and cardiovascular disease under chronic stress conditions.
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Adiponectina/metabolismo , Senescência Celular , Dipeptidil Peptidase 4/metabolismo , Células Progenitoras Endoteliais/enzimologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Isquemia/enzimologia , Neovascularização Fisiológica , Estresse Psicológico/enzimologia , Animais , Células Cultivadas , Doença Crônica , Dipeptidil Peptidase 4/deficiência , Dipeptidil Peptidase 4/genética , Modelos Animais de Doenças , Células Progenitoras Endoteliais/patologia , Isquemia/genética , Isquemia/patologia , Isquemia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteólise , Ratos Endogâmicos F344 , Ratos Transgênicos , Receptores de Adiponectina/metabolismo , Transdução de Sinais , Estresse Psicológico/genética , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologia , Fatores de Tempo , Técnicas de Cultura de TecidosRESUMO
BACKGROUND: Exercise train (ET) stimulates muscle response in pathological conditions, including aging. The molecular mechanisms by which exercise improves impaired adiponectin/adiponectin receptor 1 (AdipoR1)-related muscle actions associated with aging are poorly understood. Here we observed that in a senescence-accelerated mouse prone 10 (SAMP10) model, long-term ET modulated muscle-regenerative actions. METHODS: 25-week-old male SAMP10 mice were randomly assigned to the control and the ET (45 min/time, 3/week) groups for 4 months. Mice that were maintained in a sedentary condition served controls. RESULTS: ET ameliorated aging-related muscle changes in microstructure, mitochondria, and performance. The amounts of proteins or mRNAs for p-AMPKα, p-Akt, p-ERK1/2, p-mTOR, Bcl-XL, p-FoxO3, peroxisome proliferators-activated receptor-γ coactivator, adiponectin receptor1 (adpoR1), and cytochrome c oxidase-IV, and the numbers of CD34+ /integrin-α7+ muscle stem cells (MuSCs) and proliferating cells in the muscles and bone-marrow were enhanced by ET, whereas the levels of p-GSK-3α and gp91phox proteins and apoptotic cells were reduced by ET. The ET also resulted in increased levels of plasma adiponectin and the numbers of bone-marrow (BM)-derived circulating CD34+ /integrin-α7+ MuSCs and their functions. Integrin-α7+ MuSCs of exercised mice had improved changes of those beneficial molecules. These ET-mediated aged muscle benefits were diminished by adiponectin and AdipoR1 blocking as well as AMPK inhibition. Finally, recombinant mouse adiponectin enhanced AMPK and mTOR phosphorylations in BM-derived integrin-α7+ cells. CONCLUSIONS: These findings suggest that ET can improve aging-related impairments of BM-derived MuSC regenerative capacity and muscle metabolic alterations via an AMPK-dependent mechanism that is mediated by an adiponectin/AdipoR1 axis in SAMP10 mice.
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Adiponectina/metabolismo , Músculos/fisiologia , Mioblastos/metabolismo , Condicionamento Físico Animal , Receptores de Adiponectina/metabolismo , Regeneração , Animais , Biomarcadores , Peso Corporal , Movimento Celular , Citocinas/sangue , Lipídeos/sangue , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Força Muscular , Músculo Esquelético/fisiologia , Receptores de Adiponectina/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: DPP4 (Dipeptidyl peptidase-4)-GLP-1 (glucagon-like peptide-1) and its receptor (GLP-1R) axis has been involved in several intracellular signaling pathways. The Adrß3 (ß3-adrenergic receptor)/CXCL12 (C-X-C motif chemokine 12) signal was required for the hematopoiesis. We investigated the novel molecular requirements between DPP4-GLP-1/GLP-1 and Adrß3/CXCL12 signals in bone marrow (BM) hematopoietic stem cell (HSC) activation in response to chronic stress. METHODS AND RESULTS: Male 8-week-old mice were subjected to 4-week intermittent restrain stress and orally treated with vehicle or the DPP4 inhibitor anagliptin (30 mg/kg per day). Control mice were left undisturbed. The stress increased the blood and brain DPP4 levels, the plasma epinephrine and norepinephrine levels, and the BM niche cell Adrß3 expression, and it decreased the plasma GLP-1 levels and the brain GLP-1R and BM CXCL12 expressions. These changes were reversed by DPP4 inhibition. The stress activated BM sca-1highc-KithighCD48lowCD150high HSC proliferation, giving rise to high levels of blood leukocytes and monocytes. The stress-activated HSC proliferation was reversed by DPP4 depletion and by GLP-1R activation. Finally, the selective pharmacological blocking of Adrß3 mitigated HSC activation, accompanied by an improvement of CXCL12 gene expression in BM niche cells in response to chronic stress. CONCLUSIONS: These findings suggest that DPP4 can regulate chronic stress-induced BM HSC activation and inflammatory cell production via an Adrß3/CXCL12-dependent mechanism that is mediated by the GLP-1/GLP-1R axis, suggesting that the DPP4 inhibition or the GLP-1R stimulation may have applications for treating inflammatory diseases.
Assuntos
Encéfalo/enzimologia , Diferenciação Celular , Proliferação de Células , Dipeptidil Peptidase 4/metabolismo , Células-Tronco Hematopoéticas/enzimologia , Estresse Psicológico/enzimologia , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Doença Crônica , Dipeptidil Peptidase 4/deficiência , Dipeptidil Peptidase 4/genética , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Ratos Endogâmicos F344 , Ratos Transgênicos , Receptores Adrenérgicos beta 3/metabolismo , Restrição Física/psicologia , Transdução de Sinais , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Fatores de TempoRESUMO
Dipeptidyl peptidase-4 (DPP4) is one of the most potent mammalian serine proteases participated in the pathogenesis of subclinical atherosclerosis. Here we investigated whether the plasma soluble form of DPP4 is associated with the prevalence of coronary artery disease (CAD) with and without diabetes mellitus (DM). A cross-sectional study was conducted of 496 aged 26-81 years with (n = 362) and without (n = 134) CAD. Plasma DPP4 activity, high sensitive C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein levels were measured. The coronary atherosclerotic plaques were evaluated by coronary angiography. The CAD patients with (n = 84) and without (n = 278) DM had significantly higher DPP4 levels (11.8 ± 3.1 vs. 6.9 ± 3.5 ng/mL, P<0.01) than the nonCAD subjects. The acute coronary syndrome patients (n = 299) had elevated DPP4 levels than those with stable angina patients (n = 83). CAD patients even without DM had increased plasma DPP4 activities as compared with nonCAD subjects (10.9 ± 4.9 vs. 6.4 ± 3.1, ng/L, P< 0.01). A linear regression analysis revealed that overall, the DPP4 levels were positively associated with LCL-C and hs-CRP levels as well as syntax scores. A multiple logistic regression analysis demonstrated that plasma DPP4 activity was independent predictor of CAD (odds ratio, 1.56; 95% CI, 1.19-1.73; P<0.01). Our study shows that increased DPP4 activity levels are associated with the presence of CAD and that the plasma DPP4 level serves as a novel biomarker for CAD even without DM.
RESUMO
Cysteinyl cathepsin K (CatK) is one of the most potent mammalian collagenases involved in cardiovascular disease. Here, we investigated the clinical predictive value of serum CatK levels in patients with chronic heart failure (CHF). We examined 134 patients with CHF, measuring their serum CatK, troponin I, high-sensitive C-reactive protein, and pre-operative N-terminal pro-brain natriuretic peptide levels. The patients were divided into two groups: the 44 patients who showed a left ventricular (LV) ejection fraction (LVEF) < 40% (the "lowLVEF" group) and the 90 patients showing LVEF values ≥ 40% (the "highLVEF" group). The lowLVEF patients had significantly higher serum CatK levels compared to the highLVEF patients (58.4 ± 12.2 vs. 44.7 ± 16.4, P < 0.001). Overall, a linear regression analysis showed that CatK levels correlated negatively with LVEF (r = -0.4, P < 0.001) and positively with LV end-diastolic dimensions (r = 0.2, P < 0.01), LV end-systolic dimensions (r = 0.3, P < 0.001), and left atrial diameters (r = 0.3, P < 0.01). A multiple logistic regression analysis showed that CatK levels were independent predictors of CHF (odds ratio, 0.90; 95% confidence interval, 0.84-0.95; P < 0.01). These data indicate that elevated levels of CatK are closely associated with the presence of CHF and that the measurement of circulating CatK provides a noninvasive method of documenting and monitoring the extent of cardiac remodeling and dysfunction in patients with CHF.
Assuntos
Catepsina K/sangue , Insuficiência Cardíaca/sangue , Hipertensão/sangue , Disfunção Ventricular Esquerda/sangue , Idoso , Proteína C-Reativa/metabolismo , Ecocardiografia , Matriz Extracelular/genética , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/fisiopatologia , Lipoproteínas , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Análise de Regressão , Troponina I/sangue , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
PURPOSE: Cathepsin K is a potent collagenase implicated in human and animal atherosclerosis-based vascular remodeling. This study examined the hypothesis that serum CatK is associated with the prevalence of coronary artery disease (CAD). MATERIALS AND METHODS: Between January 2011 and December 2012, 256 consecutive subjects were enrolled from among patients who underwent coronary angiography and percutaneous coronary intervention treatment. A total of 129 age-matched subjects served as controls. RESULTS: The subjects' serum cathepsin K and high sensitive C-reactive protein (hs-CRP) and high-density lipoprotein cholesterol were measured. The patients with CAD had significantly higher serum cathepsin K levels compared to the controls (130.8±25.5 ng/mL vs. 86.9±25.5 ng/mL, p<0.001), and the patients with acute coronary syndrome had significantly higher serum cathepsin K levels compared to those with stable angina pectoris (137.1±26.9 ng/mL vs. 102.6±12.9 ng/mL, p<0.001). A linear regression analysis showed that overall, the cathepsin K levels were inversely correlated with the high-density lipoprotein levels (r=-0.29, p<0.01) and positively with hs-CRP levels (r=0.32, p<0.01). Multiple logistic regression analyses shows that cathepsin K levels were independent predictors of CAD (odds ratio, 1.76; 95% confidence interval, 1.12 to 1.56; p<0.01). CONCLUSION: These data indicated that elevated levels of cathepsin K are closely associated with the presence of CAD and that circulating cathepsin K serves a useful biomarker for CAD.