RESUMEN
Sleep deprivation (SD) has been associated with a plethora of severe pathophysiological syndromes, including gut damage, which recently has been elucidated as an outcome of the accumulation of reactive oxygen species (ROS). However, the spatiotemporal analysis conducted in this study has intriguingly shown that specific events cause harmful damage to the gut, particularly to goblet cells, before the accumulation of lethal ROS. Transcriptomic and metabolomic analyses have identified significant enrichment of metabolites related to ferroptosis in mice suffering from SD. Further analysis revealed that melatonin could rescue the ferroptotic damage in mice by suppressing lipid peroxidation associated with ALOX15 signaling. ALOX15 knockout protected the mice from the serious damage caused by SD-associated ferroptosis. These findings suggest that melatonin and ferroptosis could be targets to prevent devastating gut damage in animals exposed to SD. To sum up, this study is the first report that proposes a noncanonical modulation in SD-induced gut damage via ferroptosis with a clearly elucidated mechanism and highlights the active role of melatonin as a potential target to maximally sustain the state during SD.
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Ferroptosis , Melatonina , Ratones Noqueados , Privación de Sueño , Animales , Ratones , Melatonina/metabolismo , Melatonina/farmacología , Privación de Sueño/metabolismo , Masculino , Especies Reactivas de Oxígeno/metabolismo , Ratones Endogámicos C57BL , Peroxidación de Lípido , Araquidonato 15-Lipooxigenasa/metabolismo , Araquidonato 15-Lipooxigenasa/genética , Araquidonato 12-LipooxigenasaRESUMEN
Antimicrobial resistance (AMR) is a major threat to global public health, and antibiotic resistance genes (ARGs) are widely distributed across humans, animals, and environment. Farming environments are emerging as a key research area for ARGs and antibiotic resistant bacteria (ARB). While the skin is an important reservoir of ARGs and ARB, transmission mechanisms between farming environments and human skin remain unclear. Previous studies confirmed that swine farm environmental exposures alter skin microbiome, but the timeline of these changes is ill defined. To improve understanding of these changes and to determine the specific time, we designed a cohort study of swine farm workers and students through collected skin and environmental samples to explore the impact of daily occupational exposure in swine farm on human skin microbiome. Results indicated that exposure to livestock-associated environments where microorganisms are richer than school environment can reshape the human skin microbiome and antibiotic resistome. Exposure of 5 h was sufficient to modify the microbiome and ARG structure in workers' skin by enriching microorganisms and ARGs. These changes were preserved once formed. Further analysis indicated that ARGs carried by host microorganisms may transfer between the environment with workers' skin and have the potential to expand to the general population using farm workers as an ARG vector. These results raised concerns about potential transmission of ARGs to the broader community. Therefore, it is necessary to take corresponding intervention measures in the production process to reduce the possibility of ARGs and ARB transmission.
RESUMEN
Anthropogenic environments take an active part in shaping the human microbiome. Herein, we studied skin and nasal microbiota dynamics in response to the exposure in confined and controlled swine farms to decipher the impact of occupational exposure on microbiome formation. The microbiota of volunteers was longitudinally profiled in a 9-months survey, in which the volunteers underwent occupational exposure during 3-month internships in swine farms. By high-throughput sequencing, we showed that occupational exposure compositionally and functionally reshaped the volunteers' skin and nasal microbiota. The exposure in farm A reduced the microbial diversity of skin and nasal microbiota, whereas the microbiota of skin and nose increased after exposure in farm B. The exposure in different farms resulted in compositionally different microbial patterns, as the abundance of Actinobacteria sharply increased at expense of Firmicutes after exposure in farm A, yet Proteobacteria became the most predominant in the volunteers in farm B. The remodeled microbiota composition due to exposure in farm A appeared to stall and persist, whereas the microbiota of volunteers in farm B showed better resilience to revert to the pre-exposure state within 9 months after the exposure. Several metabolic pathways, for example, the styrene, aminobenzoate, and N-glycan biosynthesis, were significantly altered through our PICRUSt analysis, and notably, the function of beta-lactam resistance was predicted to enrich after exposure in farm A yet decrease in farm B. We proposed that the differently modified microbiota patterns might be coordinated by microbial and non-microbial factors in different swine farms, which were always environment-specific. This study highlights the active role of occupational exposure in defining the skin and nasal microbiota and sheds light on the dynamics of microbial patterns in response to environmental conversion.
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Recent studies have emphasized the role of vascular adventitia inflammation and immune response in hypertension. It has been reported that stromal cell-derived factor-1 (SDF-1) plays various biological functions through its receptors C-X-C motif chemokine receptor 4 (CXCR4) and CXCR7 in tumor growth and tissue repair. However, it is unclear that whether SDF-1/CXCR4/CXCR7 axis is involved in hypertensive vascular remodeling. In the present study, the involvement of SDF-1/CXCR4/CXCR7 axis was evaluated with lentivirus-mediated shRNA of SDF-1 and CXCR7, CXCR4 antagonist AMD3100 and CXCR7 agonist VUF11207 in angiotensin II (AngII)-induced hypertensive mice and in cultured adventitial fibroblasts (AFs). Results showed that AngII infusion markedly increased SDF-1 expressed in vascular adventitia, but not in media and endothelium. Importantly, blockade of SDF-1/CXCR4 axis strikingly potentiated AngII-induced adventitial thickening and fibrosis, as indicated by enhanced collagen I deposition. In contrast, CXCR7 shRNA largely attenuated AngII-induced adventitial thickness and fibrosis, whereas CXCR7 activation with VUF11207 significantly potentiated AngII-induced adventitial thickening and fibrosis. In consistent with these in vivo study, CXCR4 inhibition with AMD3100 and CXCR7 activation with VUF11207 aggravated AngII-induced inflammation, proliferation and migration in cultured AFs. In summary, these results suggested that SDF-1 exerted opposing effects through CXCR4 and CXCR7 in AngII-induced vascular adventitial remodeling.
Asunto(s)
Adventicia/metabolismo , Angiotensina II/metabolismo , Quimiocina CXCL12/metabolismo , Receptores CXCR4/metabolismo , Receptores CXCR/metabolismo , Animales , Bencilaminas/farmacología , Movimiento Celular/fisiología , Proliferación Celular , Colágeno/metabolismo , Ciclamas/farmacología , Modelos Animales de Enfermedad , Fibroblastos/patología , Fibrosis , Hipertensión/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Cicatrización de HeridasRESUMEN
AIMS: Aging is a risk factor for cardiovascular diseases and adaptive immunity has been implicated in angiotensin (Ang) II-induced target organ dysfunction. Herein, we sought to determine the role of T-cell senescence in Ang II-induced target organ impairment and to explore the underlying mechanisms. METHODS AND RESULTS: Flow cytometric analysis revealed that T cell derived from aged mice exhibited immunosenescence. Adoptive transfer of aged T cells to immunodeficient RAG1 KO mice accelerates Ang II-induced cardiovascular and renal fibrosis compared with young T-cell transfer. Aged T cells also promote inflammatory factor expression and superoxide production in these target organs. In vivo and in vitro studies revealed that Ang II promotes interferon-gamma (IFN-γ) production in the aged T cells comparing to young T cells. Importantly, transfer of senescent T cell that IFN-γ KO mitigates the impairment. Aged T-cell-conditioned medium stimulates inflammatory factor expression and oxidative stress in Ang II-treated renal epithelial cells compared with young T cells, and these effects of aged T-cell-conditioned medium are blunted after IFN-γ-neutralizing antibody pre-treatment. CONCLUSION: These results provide a significant insight into the contribution of senescent T cells to Ang II-induced cardiovascular dysfunction and provide an attractive possibility that targeting T cell specifically might be a potential strategy to treat elderly hypertensive patients with end-organ dysfunction.
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Aorta/inmunología , Enfermedades Cardiovasculares/inmunología , Hipertensión/inmunología , Inmunosenescencia , Enfermedades Renales/inmunología , Riñón/inmunología , Miocardio/inmunología , Linfocitos T/inmunología , Traslado Adoptivo , Angiotensina II , Animales , Aorta/metabolismo , Aorta/patología , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Línea Celular , Modelos Animales de Enfermedad , Proteínas de Homeodominio/genética , Humanos , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Hipertensión/patología , Mediadores de Inflamación/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/metabolismo , Miocardio/patología , Estrés Oxidativo , Fenotipo , Superóxidos/metabolismo , Linfocitos T/metabolismo , Linfocitos T/trasplante , Factores de TiempoRESUMEN
Vascular remodeling is an adaptive response to various stimuli, including mechanical forces, inflammatory cytokines and hormones. In the present study, we investigated the role of angiotensin II type 1 receptor (AT1R) and calcium channel in carotid artery remodeling in response to increased biomechanical forces by using the transverse aortic constriction (TAC) rat model. TAC was induced on ten-week-old male Sprague-Dawley rats and these models were treated with AT1R blocker olmesartan (1 mg/kg/day) or/and calcium channel blocker (CCB) amlodipine (0.5 mg/kg/day) for 14 days. After the treatment, the right common carotid artery proximal to the band (RCCA-B) was collected for further assay. Results showed that olmesartan, but not amlodipine, significantly prevented TAC-induced adventitial hyperplasia. Similarly, olmesartan, but not amlodipine, signifcantly prevented vascular infammation, as indicated by increased tumor necrosis factor α (TNF-α) and increased p65 phosphorylation, an indicator of nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) activation in RCCA-B. In contrast, both olmesartan and amlodipine reversed the decreased expression of endothelial nitric oxidase synthase (eNOS) and improved endothelium-dependent vasodilation, whereas combination of olmesartan and amlodipine showed no further synergistic protective effects. These results suggest that AT1R was involved in vascular remodeling and inflammation in response to pressure overload, whereas AT1R and subsequent calcium channel were involved in endothelial dysfunction.
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Amlodipino/administración & dosificación , Canales de Calcio/metabolismo , Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Traumatismos de las Arterias Carótidas/metabolismo , Imidazoles/administración & dosificación , Receptor de Angiotensina Tipo 1/metabolismo , Tetrazoles/administración & dosificación , Amlodipino/farmacología , Animales , Traumatismos de las Arterias Carótidas/etiología , Constricción Patológica , Modelos Animales de Enfermedad , Hiperplasia , Imidazoles/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Tetrazoles/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Remodelación VascularRESUMEN
BACKGROUND: Previous studies on coronavirus disease 2019 (COVID-19) have focused on populations with normal immunity, but lack data on immunocompromised populations. OBJECTIVE: To evaluate the clinical features and outcomes of COVID-19 pneumonia in kidney transplant recipients. DESIGN, SETTING, AND PARTICIPANTS: A total of 10 renal transplant recipients with laboratory-confirmed COVID-19 pneumonia were enrolled in this retrospective study. In addition, 10 of their family members diagnosed with COVID-19 pneumonia were included in the control group. INTERVENTION: Immunosuppressant reduction and low-dose methylprednisolone therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The clinical outcomes (the severity of pneumonia, recovery rate, time of virus shedding, and length of illness) were compared with the control group by statistical analysis. RESULTS AND LIMITATIONS: The clinical symptomatic, laboratory, and radiological characteristics of COVID-19 pneumonia in the renal transplant recipients were similar to those of severe COVID-19 pneumonia in the general population. The severity of COVID-19 pneumonia was greater in the transplant recipients than in the control group (five severe/three critical cases vs one severe case). Five patients developed transient renal allograft damage. After a longer time of virus shedding (28.4 ± 9.3 vs 12.2 ± 4.6 d in the control group) and a longer course of illness (35.3 ± 8.3 vs 18.8 ± 10.5 d in the control group), nine of the 10 transplant patients recovered successfully after treatment. One patient developed acute renal graft failure and died of progressive respiratory failure. CONCLUSIONS: Kidney transplant recipients had more severe COVID-19 pneumonia than the general population, but most of them recovered after a prolonged clinical course and virus shedding. Findings from this small group of cases may have important implications for the treatment of COVID-19 pneumonia in immunosuppressed populations. PATIENT SUMMARY: Immunosuppressed transplant recipients with coronavirus disease 2019 infection had more severe pneumonia, but most of them still achieved a good prognosis after appropriate treatment.
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Antivirales/administración & dosificación , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Glucocorticoides/administración & dosificación , Huésped Inmunocomprometido , Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Metilprednisolona/administración & dosificación , Infecciones Oportunistas/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Receptores de Trasplantes , Adulto , Anciano , Antivirales/efectos adversos , Betacoronavirus/inmunología , Betacoronavirus/aislamiento & purificación , COVID-19 , Prueba de COVID-19 , China , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Femenino , Glucocorticoides/efectos adversos , Humanos , Inmunosupresores/administración & dosificación , Trasplante de Riñón/mortalidad , Masculino , Metilprednisolona/efectos adversos , Persona de Mediana Edad , Ventilación no Invasiva , Infecciones Oportunistas/mortalidad , Infecciones Oportunistas/terapia , Infecciones Oportunistas/virología , Terapia por Inhalación de Oxígeno , Pandemias , Neumonía Viral/mortalidad , Neumonía Viral/virología , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Esparcimiento de Virus , Adulto Joven , Tratamiento Farmacológico de COVID-19RESUMEN
Cardiac fibrosis is a common feature in chronic hypertension patients with advanced heart failure, and endothelial-tomesenchymal transition (EndMT) is known to promote Angiotensin II (Ang II)-mediated cardiac fibrosis. Previous studies have suggested a potential role for the transcription factor, ETS-1, in Ang II-mediated cardiac remodeling, however the mechanism are not well defined. In this study, we found that mice with endothelial Ets-1 deletion showed reduced cardiac fibrosis and hypertrophy following Ang II infusion. The reduced cardiac fibrosis was accompanied by decreased expression of fibrotic matrix genes, reduced EndMT with decreased Snail, Slug, Twist, and ZEB1 expression, as well as reduced cardiac hypertrophy and expression of hypertrophyassociated genes was observed. In vitro studies using cultured H5V cells further confirmed that ETS-1 knockdown inhibited TGF-ß1-induced EndMT. This study revealed that deletion of endothelial Ets-1 attenuated Ang II-induced cardiac fibrosis via inhibition of EndMT, indicating an important ETS-1 function in mediating EndMT. Inhibition of ETS-1 could be a potential therapeutic strategy for treatment of heart failure secondary to chronic hypertension. [BMB Reports 2019; 52(10): 595-600].
Asunto(s)
Transición Epitelial-Mesenquimal , Miocardio/patología , Proteína Proto-Oncogénica c-ets-1/metabolismo , Angiotensina II , Animales , Cardiomegalia/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Fibrosis , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Proto-Oncogénica c-ets-1/genética , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta1/farmacología , Factores de Transcripción Twist/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismoRESUMEN
Ets-1 is a member of the Ets family of transcription factors and has critical roles in multiple biological functions. Structural kidney defects occur at an increased frequency in Jacobsen syndrome (OMIM #147791), a rare chromosomal disorder caused by deletions in distal 11q, implicating at least one causal gene in distal 11q. In this study, we define an 8.1 Mb "critical region" for kidney defects in Jacobsen syndrome, which spans ~50 genes. We demonstrate that gene-targeted deletion of Ets-1 in mice results in some of the most common congenital kidney defects occurring in Jacobsen syndrome, including: duplicated kidney, hypoplastic kidney, and dilated renal pelvis and calyces. Taken together, our results implicate Ets-1 in normal mammalian kidney development and, potentially, in the pathogenesis of some of the most common types of human structural kidney defects.
Asunto(s)
Síndrome de Deleción Distal 11q de Jacobsen/genética , Riñón/patología , Proteína Proto-Oncogénica c-ets-1/genética , Animales , Cromosomas Humanos Par 11 , Modelos Animales de Enfermedad , Eliminación de Gen , Marcación de Gen , Predisposición Genética a la Enfermedad , Humanos , Síndrome de Deleción Distal 11q de Jacobsen/patología , Riñón/anomalías , Riñón/crecimiento & desarrollo , Ratones , Eliminación de Secuencia/genéticaRESUMEN
Thoracic aorta perivascular adipose tissue (T-PVAT) has critical roles in regulating vascular homeostasis. However, the developmental characteristics and cellular lineage of adipocyte in the T-PVAT remain unclear. We show that T-PVAT contains three long strip-shaped fat depots, anterior T-PVAT (A-T-PVAT), left lateral T-PVAT (LL-T-PVAT), and right lateral T-PVAT (RL-T-PVAT). A-T-PVAT displays a distinct transcriptional profile and developmental origin compared to the two lateral T-PVATs (L-T-PVAT). Lineage tracing studies indicate that A-T-PVAT adipocytes are primarily derived from SM22α+ progenitors, whereas L-T-PVAT contains both SM22α+ and Myf5+ cells. We also show that L-T-PVAT contains more UCP1+ brown adipocytes than A-T-PVAT, and L-T-PVAT exerts a greater relaxing effect on aorta than A-T-PVAT. Angiotensin II-infused hypertensive mice display greater macrophage infiltration into A-T-PVAT than L-T-PVAT. These combined results indicate that L-T-PVAT has a distinct development from A-T-PVAT with different cellular lineage, and suggest that L-T-PVAT and A-T-PVAT have different physiological and pathological functions.
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Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Aorta Torácica/metabolismo , Perfilación de la Expresión Génica/métodos , Tejido Adiposo/citología , Tejido Adiposo/crecimiento & desarrollo , Animales , Diferenciación Celular/genética , Linaje de la Célula/genética , Ontología de Genes , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Factor 5 Regulador Miogénico/genética , Factor 5 Regulador Miogénico/metabolismo , Células Madre/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMEN
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary artery (PA) remodeling. T helper 2 cell (Th2) immune response is involved in PA remodeling during PAH progression. Here, we found that CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cell) expression was up-regulated in circulating CD3+CD4+ T cells in patients with idiopathic PAH and in rodent PAH models. CRTH2 disruption dramatically ameliorated PA remodeling and pulmonary hypertension in different PAH mouse models. CRTH2 deficiency suppressed Th2 activation, including IL-4 and IL-13 secretion. Both CRTH2+/+ bone marrow reconstitution and CRTH2+/+ CD4+ T cell adoptive transfer deteriorated hypoxia + ovalbumin-induced PAH in CRTH2-/- mice, which was reversed by dual neutralization of IL-4 and IL-13. CRTH2 inhibition alleviated established PAH in mice by repressing Th2 activity. In culture, CRTH2 activation in Th2 cells promoted pulmonary arterial smooth muscle cell proliferation through activation of STAT6. These results demonstrate the critical role of CRTH2-mediated Th2 response in PAH pathogenesis and highlight the CRTH2 receptor as a potential therapeutic target for PAH.
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Hipertensión Pulmonar/inmunología , Activación de Linfocitos/inmunología , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Células Th2/inmunología , Traslado Adoptivo , Adulto , Animales , Anticuerpos/farmacología , Presión Sanguínea/efectos de los fármacos , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Proliferación Celular/efectos de los fármacos , Quimera , Enfermedad Crónica , Modelos Animales de Enfermedad , Femenino , Eliminación de Gen , Humanos , Hipertensión Pulmonar/fisiopatología , Hipoxia/complicaciones , Hipoxia/fisiopatología , Inmunidad/efectos de los fármacos , Indoles , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/fisiopatología , Masculino , Ratones , Ovalbúmina , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Pirroles , Receptores Inmunológicos/deficiencia , Receptores de Prostaglandina/deficiencia , Factor de Transcripción STAT6/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Functional perivascular adipose tissue (PVAT) is necessary to maintain vascular physiology through both mechanical support and endocrine or paracrine ways. PVAT shows a brown adipose tissue (BAT)-like feature and the browning level of PVAT is dependent on the anatomic location and species. However, it is not clear whether PVAT browning is involved in the vascular tone regulation in spontaneously hypertensive rats (SHRs). In the present study, we aimed to illustrate the effect of aging on PVAT browning and subsequent vasomotor reaction in SHRs. Herein we utilized histological staining and western blot to detect the characteristics of thoracic PVAT (tPVAT) in 8-week-old and 16-week-old SHR and Wistar-Kyoto (WKY) rats. We also detected vascular reactivity analysis to determine the effect of tPVAT on vasomotor reaction during aging. The results showed that tPVAT had a similar phenotype to BAT, including smaller adipocyte size and positive uncoupling protein-1 (UCP1) staining. Interestingly, the tPVAT of 8-week-old SHR showed increased BAT phenotypic marker expression compared to WKY, whereas the browning level of tPVAT had a more dramatic decrease from 8 to 16 weeks of age in SHR than age-matched WKY rats. The vasodilation effect of tPVAT on aortas had no significant difference in 8-week-old WKY and SHR, whereas this effect is obviously decreased in 16-week-old SHR compared to WKY. In contrast, tPVAT showed a similar vasoconstriction effect in 8- or 16-week-old WKY and SHR rats. Moreover, we identified an important vasodilator adenosine, which regulates adipocyte browning and may be a potential PVAT-derived relaxing factor. Adenosine is dramatically decreased from 8 to 16 weeks of age in the tPVAT of SHR. In summary, aging is associated with a decrease of tPVAT browning and adenosine production in SHR rats. These may result in attenuated vasodilation effect of the tPVAT in SHR during aging.
RESUMEN
Aims: Cardiac myofibroblasts (CMFs) play a crucial role in the progression of pathological fibrotic cardiac remodelling. The expression of osteoglycin (OGN) is increased in diseased hearts; however, the role of OGN in pathological cardiac remodelling is not understood. Here, we sought to determine the effect of OGN on cardiac interstitial fibrosis and investigate the molecular mechanisms of OGN in CMF activation and matrix production. Methods and results: We found that OGN expression was significantly upregulated in mouse hearts in response to chronic 14-day angiotensin II (Ang II) infusion. Mice lacking OGN (OGN-/-) exhibited enhanced cardiac interstitial fibrosis and significantly more severe cardiac dysfunction following Ang II infusion compared to wild-type mice. OGN deficiency did not alter blood pressure, nor had effect on transforming growth factor-beta signalling activation, but presented with increased proliferative activity in hearts. In vitro studies with isolated CMFs revealed that OGN deficiency significantly increased proliferation and migration and enhanced the transactivation of epidermal growth factor receptor (EGFR) signalling by Ang II. On the other hand, OGN overexpression in CMFs decreased their proliferation and migration via reducing EGFR activation. Overexpression of OGN also suppressed the shedding of membrane anchored EGFR ligand. Moreover, OGN was found to interact with a lysophosphatidic acid (LPA) receptor isoform 3 and thus to attenuate EGFR transactivation through blocking cell surface translocation of membrane type 1 matrix metalloproteinase (MT1-MMP) and subsequent pro-MMP-2 activation in a Ras homolog gene family, member A (RhoA)/Rho-associated, coiled-coil containing protein kinase (ROCK)-dependent manner. Conclusion: These findings suggest that OGN negatively regulates cardiac fibrotic remodelling by attenuating CMF proliferation and migration through LPA3-mediated and Rho/ROCK-dependent inhibition of MT1-MMP translocation, MMP2 activation and EGFR transactivation.
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Cardiomegalia/enzimología , Proliferación Celular , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Miofibroblastos/enzimología , Receptores del Ácido Lisofosfatídico/metabolismo , Remodelación Ventricular , Angiotensina II , Animales , Cardiomegalia/inducido químicamente , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Movimiento Celular , Células Cultivadas , Modelos Animales de Enfermedad , Receptores ErbB/metabolismo , Fibrosis , Hipertensión/inducido químicamente , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Péptidos y Proteínas de Señalización Intercelular/genética , Metaloproteinasa 14 de la Matriz/metabolismo , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Miofibroblastos/patología , Receptor Cross-Talk , Transducción de Señal , Proteínas de Unión al GTP rho/metabolismo , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoARESUMEN
RATIONALE: Inflammation and immunity play crucial roles in the development of hypertension. Complement activation-mediated innate immune response is involved in the regulation of hypertension and target-organ damage. However, whether complement-mediated T-cell functions could regulate blood pressure elevation in hypertension is still unclear. OBJECTIVE: We aim to determine whether C3aR (complement component 3a receptor) and C5aR (complement component 5a receptor) could regulate blood pressure via modulating regulatory T cells (Tregs). METHODS AND RESULTS: We showed that angiotensin II (Ang II)-induced hypertension resulted in an elevated expression of C3aR and C5aR in Foxp3 (forkhead box P3)+ Tregs. By using C3aR and C5aR DKO (double knockout) mice, we showed that C3aR and C5aR deficiency together strikingly decreased both systolic and diastolic blood pressure in response to Ang II compared with WT (wild type), single C3aR-deficient (C3aR-/-), or C5aR-deficient (C5aR-/-) mice. Flow cytometric analysis showed that Ang II-induced Treg reduction in the kidney and blood was also blocked in DKO mice. Histological analysis indicated that renal and vascular structure remodeling and damage after Ang II treatment were attenuated in DKO mice compared with WT mice. In vitro, Ang II was able to stimulate C3aR and C5aR expression in cultured CD4+CD25+ natural Tregs. CD3 and CD28 antibody stimuli downregulated Foxp3 expression in WT but not DKO Tregs. More important, depletion of Tregs with CD25 antibody abolished the protective effects against Ang II-induced hypertension and target-organ damage in DKO mice. Adoptive transfer of DKO Tregs showed much more profound protective effects against Ang II-induced hypertension than WT Treg transfer. Furthermore, we demonstrated that C5aR expression in Foxp3+ Tregs was higher in hypertensive patients compared with normotensive individuals. CONCLUSIONS: C3aR and C5aR DKO-mediated Treg function prevents Ang II-induced hypertension and target-organ damage. Targeting C3aR and C5aR in Tregs specifically may be an alternative novel approach for hypertension treatment.
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Hipertensión/inmunología , Receptor de Anafilatoxina C5a/deficiencia , Receptores de Complemento 3b/deficiencia , Linfocitos T Reguladores/inmunología , Angiotensina II/toxicidad , Animales , Células Cultivadas , Hipertensión/etiología , Hipertensión/genética , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
Apelin has been proved to be a critical mediator of vascular function and homeostasis. Here, we investigated roles of Apelin in aortic remodeling and fibrosis in rats with transverse aortic constriction (TAC). Male Sprague-Dawley rats were subjected to TAC and then randomized to daily deliver Apelin-13 (50µg/kg) or angiotensin type 1 receptor (AT1) blocker Irbesartan (50mg/kg) for 4 weeks. Pressure overload resulted in myocardial hypertrophy, systolic dysfunction, aortic remodeling and adventitial fibrosis with reduced levels of Apelin in ascending aortas of rat after TAC compared with sham-operated group. These changes were associated with marked increases in levels of miRNA-122, TGFß1, CTGF, NFAT5, LGR4, and ß-catenin. More importantly, Apelin and Irbesartan treatment strikingly prevented TAC-mediated aortic remodeling and adventitial fibrosis in pressure overloaded rats by blocking AT1 receptor and miRNA-122 levels and repressing activation of the CTGF-NFAT5 and LGR4-ß-catenin signaling. In cultured primary rat adventitial fibroblasts, exposure to angiotensin II (100nmolL-1) led to significant increases in cellular migration and levels of TGFß1, CTGF, NFAT5, LGR4 and ß-catenin, which were effectively reversed by pre-treatment with Apelin (100nmolL-1) and miRNA-122 inhibitor (50nmolL-1). In conclusion, Apelin counterregulated against TAC-mediated ascending aortic remodeling and angiotensin II-induced promotion of cellular migration by blocking AT1 receptor and miRNA-122 levels and preventing activation of the TGFß1-CTGF-NFAT5 and LGR4-ß-catenin signaling, ultimately contributing to attenuation of aortic adventitial fibrosis. Our data point to Apelin as an important regulator of aortic remodeling and adventitial fibrosis and a promising target for vasoprotective therapies.
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Adventicia/patología , Aorta/patología , Aneurisma de la Aorta Torácica/patología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Animales , Aneurisma de la Aorta Torácica/metabolismo , Cardiomegalia/metabolismo , Células Cultivadas , Fibrosis , Péptidos y Proteínas de Señalización Intercelular/farmacología , Masculino , MicroARNs/metabolismo , Miocardio/metabolismo , Miocardio/patología , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo , Factores de Transcripción/metabolismo , Remodelación Vascular , Remodelación Ventricular , Vía de Señalización Wnt , beta Catenina/metabolismoRESUMEN
The sympathetic nervous system interacts with the renin-angiotensin-aldosterone system (RAAS) contributing to cardiovascular diseases. In this study, we sought to determine if renal denervation (RDN) inhibits aldosterone expression and associated cardiovascular pathophysiological changes in angiotensin II (Ang II)-induced hypertension. Bilateral RDN or SHAM operation was performed before chronic 14-day Ang II subcutaneous infusion (200ng/kg/min) in male Sprague-Dawley rats. Bilateral RDN blunted Ang II-induced hypertension and ameliorated the mesenteric vascular dysfunction. Cardiovascular hypertrophy in response to Ang II was significantly attenuated by RDN as shown by histopathology and transthoracic echocardiography. Moreover, Ang II-induced vascular and myocardial inflammation and fibrosis were suppressed by RDN with concurrent decrease in fibronectin and collagen deposition, macrophage infiltration, and MCP-1 expression. Interestingly, RDN also inhibited Ang II-induced aldosterone expression in the plasma, kidney and heart. This was associated with the reduction of calcitonin gene-related peptide (CGRP) in the adrenal gland. Ang II promoted aldosterone secretion which was partly attenuated by CGRP in the adrenocortical cell line, suggesting a protective role of CGRP in this model. Activation of transforming growth factor-ß (TGF-ß)/Smad and mitogen-activated protein kinases (MAPKs) signaling pathway was both inhibited by RDN especially in the heart. These results suggest that the regulation of the renal sympathetic nerve in Ang II-induced hypertension and associated cardiovascular pathophysiological changes is likely mediated by aldosterone, with CGRP involvement.
Asunto(s)
Aldosterona/metabolismo , Corazón/fisiopatología , Hipertensión/fisiopatología , Riñón/metabolismo , Aldosterona/sangre , Angiotensina II , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Línea Celular Tumoral , Desnervación , Humanos , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Riñón/inervación , Masculino , Ratas Sprague-Dawley , Sistema Renina-Angiotensina/fisiología , Transducción de Señal/fisiologíaRESUMEN
Beta3 adrenergic receptor (ADRB3) mediates vessel relaxation in the endothelium while it modulates lipolysis in the adipose tissue. However, the function and regulation mechanism of ADRB3 in the perivascular adipose tissue (PVAT), especially in hypertension, is still unclear. We show that ADRB3 protein is upregulated in the PVAT of deoxycorticosterone acetate-salt (DOCA-salt) hypertensive mice, with the characteristics of PVAT browning and increased uncoupling protein 1 (UCP1) expression. Inhibition of ADRB3 with selective antagonist SR59230A caused serious vascular injury in vivo, even though UCP1 expression was downregulated. ADRB3 protein was regulated by let-7b, which was decreased in the PVAT of the DOCA-salt group. These data reveal that ADRB3 in PVAT contributes to vascular function in the progression of hypertension.
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Hipertensión/complicaciones , Hipertensión/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Lesiones del Sistema Vascular/etiología , Lesiones del Sistema Vascular/metabolismo , Regiones no Traducidas 3' , Células 3T3-L1 , Tejido Adiposo/irrigación sanguínea , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Antagonistas de Receptores Adrenérgicos beta 3/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/lesiones , Aorta Torácica/metabolismo , Secuencia de Bases , Sitios de Unión/genética , Células Cultivadas , Acetato de Desoxicorticosterona , Humanos , Hipertensión/genética , Canales Iónicos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Mitocondriales/metabolismo , Datos de Secuencia Molecular , Propanolaminas/farmacología , Receptores Adrenérgicos beta 3/genética , Proteína Desacopladora 1 , Lesiones del Sistema Vascular/genéticaRESUMEN
Activating transcription factor 3 (ATF3) is an adaptive-response protein induced by various environmental stresses and is implicated in the pathogenesis of many disease states. However, the role of ATF3 SUMOylation in hypertension-induced vascular injury remains poorly understood. Here we investigated the function of ATF3 SUMOylation in vascular endothelial cells (ECs). The expression of ATF3 and small ubiquitin-like modifier 1 (SUMO1) was increased in angiotensin II (Ang II)-induced human umbilical vein endothelial cells (HUVECs). Microscopic analyses further revealed that the expression of ATF3 and SUMO1 is upregulated and colocalized in the endothelium of thoracic aortas from Ang II-induced hypertensive mice. However, Ang II-induced upregulation of ATF3 and SUMO1 in vitro and in vivo was blocked by Ang II type I receptor antagonist olmesartan. Moreover, Ang II induced ATF3 SUMOylation at lysine 42, which is SUMO1 dependent. ATF3 SUMOylation attenuated ATF3 ubiquitination and in turn promoted ATF3 protein stability. ATF3 or SUMO1 knockdown inhibited Ang II-induced expression of inflammatory molecules such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8. Wild type ATF3 but not ATF3-K42R (SUMOylation defective mutant) reduced the production of nitric oxide (NO), a key indicator of EC function. Consistently, ginkgolic acid, an inhibitor of SUMOylation, increased NO production in HUVECs and significantly improved vasodilatation of aorta from Ang II-induced hypertensive mice. Our findings demonstrated that ATF3 SUMOylation is involved in Ang II-induced EC inflammation and dysfunction in vitro and in vivo through inhibiting ATF3 ubiquitination and increasing ATF3 protein stability.
Asunto(s)
Factor de Transcripción Activador 3/genética , Angiotensina II/metabolismo , Aorta/metabolismo , Inflamación/genética , Receptor de Angiotensina Tipo 1/genética , Proteína SUMO-1/genética , Factor de Transcripción Activador 3/biosíntesis , Angiotensina II/genética , Animales , Aorta/patología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células Endoteliales de la Vena Umbilical Humana , Humanos , Imidazoles/administración & dosificación , Inflamación/patología , Interleucina-6/biosíntesis , Ratones , Óxido Nítrico/biosíntesis , Proteína SUMO-1/biosíntesis , Sumoilación/genética , Tetrazoles/administración & dosificación , Vasodilatación/genéticaRESUMEN
Nanolayered lithium-rich oxide doped with spinel phase is synthesized by acidic sucrose-assistant sol-gel combustion and evaluated as the cathode of a high-energy-density lithium ion battery. Physical characterizations indicate that the as-synthesized oxide (LR-SN) is composed of uniform and separated nanoparticles of about 200 nm, which are doped with about 7% spinel phase, compared to the large aggregated ones of the product (LR) synthesized under the same condition but without any assistance. Charge/discharge demonstrates that LR-SN exhibits excellent rate capability and cyclic stability: delivering an average discharge capacity of 246 mAh g(-1) at 0.2 C (1C = 250 mA g(-1)) and earning a capacity retention of 92% after 100 cycles at 4 C in the lithium anode-based half cell, compared to the 227 mA g(-1) and the 63% of LR, respectively. Even in the graphite anode-based full cell, LR-SN still delivers a capacity of as high as 253 mAh g(-1) at 0.1 C, corresponding to a specific energy density of 801 Wh kg(-1), which are the best among those that have been reported in the literature. The separated nanoparticles of the LR-SN provide large sites for charge transfer, while the spinel phase doped in the nanoparticles facilitates lithium ion diffusion and maintains the stability of the layered structure during cycling.