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1.
Cardiovasc Res ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34528097

RESUMO

AIMS: Endothelial cell dysfunction drives the initiation and pathogenesis of pulmonary arterial hypertension (PAH). We aimed to characterise endothelial cell (EC) dynamics in PAH at single-cell resolution. METHODS AND RESULTS: We carried out single-cell RNA sequencing (scRNA-seq) of lung ECs isolated from an EC lineage-tracing mouse model in Control and SU5416/Hypoxia-induced PAH conditions. EC populations corresponding to distinct lung vessel types, including two discrete capillary populations, were identified in both Control and PAH mice. Differential gene expression analysis revealed global PAH-induced EC changes that were confirmed by bulk RNA-seq. This included upregulation of the major histocompatibility complex class II pathway, supporting a role for ECs in the inflammatory response in PAH. We also identified a PAH response specific to the second capillary EC population including upregulation of genes involved in cell death, cell motility and angiogenesis. Interestingly, four genes with genetic variants associated with PAH were dysregulated in mouse ECs in PAH. To compare relevance across PAH models and species, we performed a detailed analysis of EC heterogeneity and response to PAH in rats and humans through whole-lung PAH scRNA-seq datasets, revealing that 51% of up-regulated mouse genes were also up-regulated in rat or human PAH. We identified promising new candidates to target endothelial dysfunction including CD74, the knockdown of which regulates EC proliferation and barrier integrity in vitro. Finally, with an in silico cell ordering approach, we identified zonation-dependent changes across the arteriovenous axis in mouse PAH and showed upregulation of the Serine/threonine-protein kinase Sgk1 at the junction between the macro- and micro-vasculature. CONCLUSIONS: This study uncovers PAH-induced EC transcriptomic changes at a high resolution, revealing novel targets for potential therapeutic candidate development.

2.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299240

RESUMO

Glucocorticoids are steroid hormones with key roles in the regulation of many physiological systems including energy homeostasis and immunity. However, chronic glucocorticoid excess, highlighted in Cushing's syndrome, is established as being associated with increased cardiovascular disease (CVD) risk. Atherosclerosis is the major cause of CVD, leading to complications including coronary artery disease, myocardial infarction and heart failure. While the associations between glucocorticoid excess and increased prevalence of these complications are well established, the mechanisms underlying the role of glucocorticoids in development of atheroma are unclear. This review aims to better understand the importance of glucocorticoids in atherosclerosis and to dissect their cell-specific effects on key processes (e.g., contractility, remodelling and lesion development). Clinical and pre-clinical studies have shown both athero-protective and pro-atherogenic responses to glucocorticoids, effects dependent upon their multifactorial actions. Evidence indicates regulation of glucocorticoid bioavailability at the vasculature is complex, with local delivery, pre-receptor metabolism, and receptor expression contributing to responses linked to vascular remodelling and inflammation. Further investigations are required to clarify the mechanisms through which endogenous, local glucocorticoid action and systemic glucocorticoid treatment promote/inhibit atherosclerosis. This will provide greater insights into the potential benefit of glucocorticoid targeted approaches in the treatment of cardiovascular disease.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/fisiopatologia , Glucocorticoides/farmacologia , Aterosclerose/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Síndrome de Cushing , Glucocorticoides/metabolismo , Humanos , Inflamação/tratamento farmacológico , Receptores de Glucocorticoides/metabolismo , Fatores de Risco
3.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924852

RESUMO

Sex differences in cardiovascular disease (CVD), including aortic stenosis, atherosclerosis and cardiovascular calcification, are well documented. High levels of testosterone, the primary male sex hormone, are associated with increased risk of cardiovascular calcification, whilst estrogen, the primary female sex hormone, is considered cardioprotective. Current understanding of sexual dimorphism in cardiovascular calcification is still very limited. This review assesses the evidence that the actions of sex hormones influence the development of cardiovascular calcification. We address the current question of whether sex hormones could play a role in the sexual dimorphism seen in cardiovascular calcification, by discussing potential mechanisms of actions of sex hormones and evidence in pre-clinical research. More advanced investigations and understanding of sex hormones in calcification could provide a better translational outcome for those suffering with cardiovascular calcification.


Assuntos
Androgênios/fisiologia , Estrogênios/fisiologia , Doenças das Valvas Cardíacas/etiologia , Calcificação Vascular/etiologia , Animais , Modelos Animais de Doenças , Doenças das Valvas Cardíacas/metabolismo , Humanos , Transdução de Sinais , Calcificação Vascular/metabolismo
7.
Eur Heart J Cardiovasc Imaging ; 21(6): 673-682, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408105

RESUMO

AIMS: Cardiovascular thrombosis is responsible a quarter of deaths annually worldwide. Current imaging methods for cardiovascular thrombosis focus on anatomical identification of thrombus but cannot determine thrombus age or activity. Molecular imaging techniques hold promise for identification and quantification of thrombosis in vivo. Our objective was to assess a novel optical and positron-emitting probe targeting Factor XIIIa (ENC2015) as biomarker of active thrombus formation. METHODS AND RESULTS: Optical and positron-emitting ENC2015 probes were assessed ex vivo using blood drawn from human volunteers and passed through perfusion chambers containing denuded porcine aorta as a model of arterial injury. Specificity of ENC2015 was established with co-infusion of a factor XIIIa inhibitor. In vivo18F-ENC2015 biodistribution, kinetics, radiometabolism, and thrombus binding were characterized in rats. Both Cy5 and fluorine-18 labelled ENC2015 rapidly and specifically bound to thrombi. Thrombus uptake was inhibited by a factor XIIIa inhibitor. 18F-ENC2015 remained unmetabolized over 8 h when incubated in ex vivo human blood. In vivo, 42% of parent radiotracer remained in blood 60 min post-administration. Biodistribution studies demonstrated rapid clearance from tissues with elimination via the urinary system. In vivo,18F-ENC2015 uptake was markedly increased in the thrombosed carotid artery compared to the contralateral patent artery (mean standard uptake value ratio of 2.40 vs. 0.74, P < 0.0001). CONCLUSION: ENC2015 rapidly and selectively binds to acute thrombus in both an ex vivo human translational model and an in vivo rodent model of arterial thrombosis. This probe holds promise for the non-invasive identification of thrombus formation in cardiovascular disease.


Assuntos
Fator XIIIa , Trombose , Animais , Fibrina/metabolismo , Imagem Molecular , Ratos , Suínos , Trombose/diagnóstico por imagem , Distribuição Tecidual
9.
J Physiol ; 597(3): 767-780, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30537108

RESUMO

KEY POINTS: Type 1 diabetes mellitus increases cardiovascular risk; hypertension amplifies this risk, while pressure natriuresis regulates long-term blood pressure. We induced type 1 diabetes in rats by streptozotocin injection and demonstrated a substantial impairment of pressure natriuresis: acute increases in blood pressure did not increase renal medullary blood flow, tubular sodium reabsorption was not downregulated, and proximal tubule sodium reabsorption, measured by lithium clearance, was unaffected. Insulin reduced blood glucose in diabetic rats, and rescued the pressure natriuresis response without influencing lithium clearance, but did not restore medullary blood flow. Radiotelemetry showed that diastolic blood pressure was increased in diabetic rats, and its diurnal variation was reduced. Increases in medullary blood flow and decreases in distal tubule sodium reabsorption that offset acute rises in BP are impaired in early type 1 diabetes, and this impairment could be a target for preventing hypertension in type 1 diabetes. ABSTRACT: Type 1 diabetes mellitus (T1DM) substantially increases cardiovascular risk, and hypertension amplifies this risk. Blood pressure (BP) and body sodium homeostasis are linked. T1DM patients have increased total exchangeable sodium, correlating directly with BP. Pressure natriuresis is an important physiological regulator of BP. We hypothesised that pressure natriuresis would be impaired, and BP increased, in the early phase of T1DM. Male Sprague-Dawley rats were injected with streptozotocin (30-45 mg/kg) or citrate vehicle. After 3 weeks, pressure natriuresis was induced by serial arterial ligation. In non-diabetic controls, this increased fractional excretion of sodium from ∼1% to ∼25% of the filtered load (P < 0.01); in T1DM rats, the response was significantly blunted, peaking at only ∼3% (P < 0.01). Mechanistically, normal lithium clearance suggested that distal tubule sodium reabsorption was not downregulated with increased BP in T1DM rats. The pressure dependence of renal medullary perfusion, considered a key factor in the integrated response, was abolished. Insulin therapy rescued the natriuretic response in diabetic rats, restoring normal downregulation of tubular sodium reabsorption when BP was increased. However, the pressure dependence of medullary perfusion was not restored, suggesting persistent vascular dysfunction despite glycaemic control. Radiotelemetry showed that T1DM did not affect systolic BP, but mean diastolic BP was ∼5 mmHg higher than in non-diabetic controls (P < 0.01), and normal diurnal variation was reduced. In conclusion, functional impairment of renal sodium and BP homeostasis is an early manifestation of T1DM, preceding hypertension and nephropathy. Early intervention to restore pressure natriuresis in T1DM may complement reductions in cardiovascular risk achieved with glycaemic control.


Assuntos
Pressão Sanguínea/fisiologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Natriurese/fisiologia , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Regulação para Baixo/fisiologia , Hemodinâmica/fisiologia , Hipertensão/fisiopatologia , Rim/metabolismo , Rim/fisiopatologia , Lítio/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Circulação Renal/fisiologia , Sódio/metabolismo
10.
Br J Cancer ; 119(12): 1508-1517, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30374123

RESUMO

BACKGROUND: The Wilms' tumour protein (WT1), which influences tumour development and angiogenesis, is a promising therapeutic target in breast cancer. We hypothesised that WT1 expression would vary in endothelial cells in distinct sub-classifications of breast cancer. METHODS: WT1 expression and vascular density were quantified by immunohistochemical analysis of human (n = 57) and murine breast cancers. Human tumours were sub-classified by histopathological grade, ER status and HER2 enrichment. RESULTS: WT1 was identified in endothelial (and epithelial and smooth muscle) cells in tumours and tumour-free tissues (controls) from patients and mice with breast cancer. WT1 expression was higher in tumours than in controls, but this was not due to increased endothelial WT1. Vascular WT1 in cancers decreased as histopathological grade increased. WT1 was higher in ER-positive versus ER-negative cancers. Strikingly, reduced WT1 expression in controls correlated with an increased Nottingham Prognostic Index score. CONCLUSIONS: Expression of WT1 is increased in breast cancers but this is not limited to the vascular compartment. The association between reduced WT1 in tumour-free tissue and poor prognosis suggests a protective role for WT1 in the healthy breast.


Assuntos
Neoplasias da Mama/patologia , Proteínas WT1/análise , Animais , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Feminino , Humanos , Camundongos , Gradação de Tumores , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Proteínas WT1/fisiologia
11.
Endocrinology ; 159(11): 3791-3800, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30289445

RESUMO

Equine Cushing disease [pituitary pars intermedia dysfunction (PPID)] is a common condition of older horses, but its pathophysiology is complex and poorly understood. In contrast to pituitary-dependent hyperadrenocorticism in other species, PPID is characterized by elevated plasma ACTH but not elevated plasma cortisol. In this study, we address this paradox and the hypothesis that PPID is a syndrome of ACTH excess in which there is dysregulation of peripheral glucocorticoid metabolism and binding. In 14 horses with PPID compared with 15 healthy controls, we show that in plasma, cortisol levels and cortisol binding to corticosteroid binding globulin were not different; in urine, glucocorticoid and androgen metabolites were increased up to fourfold; in liver, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) expression was reduced; in perirenal adipose tissue, 11ß-HSD1 and carbonyl reductase 1 expression was increased; and tissue cortisol levels were not measurably different. The combination of normal plasma cortisol with markedly enhanced urinary cortisol metabolite excretion and dysregulated tissue-specific steroid-metabolizing enzymes suggests that cortisol clearance is increased in horses with PPID. We infer that the ACTH excess may be compensatory and pituitary pathology and autonomous secretion may be a secondary rather than primary pathology. It is possible that successful therapy in PPID may be targeted either at lowering ACTH or, paradoxically, at reducing cortisol clearance.


Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Doenças dos Cavalos/metabolismo , Hidrocortisona/metabolismo , Hipersecreção Hipofisária de ACTH/veterinária , Adeno-Hipófise Parte Intermédia/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Tecido Adiposo/metabolismo , Androgênios/metabolismo , Androgênios/urina , Animais , Carbonil Redutase (NADPH)/metabolismo , Estudos de Casos e Controles , Glucocorticoides/metabolismo , Glucocorticoides/urina , Cavalos , Hidrocortisona/urina , Fígado/metabolismo , Hipersecreção Hipofisária de ACTH/metabolismo , Transcortina/metabolismo
12.
Sci Rep ; 8(1): 11532, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30068994

RESUMO

Leukemia inhibitory factor (LIF), a pleiotropic cytokine belonging to the interleukin-6 family, is most often noted for its role in maintaining the balance between stem cell proliferation and differentiation. In rodents, LIF is expressed in both the fetal and adult testis; with the peritubular myoid (PTM) cells thought to be the main site of production. Given their anatomical location, LIF produced by PTM cells may act both on intratubular and interstitial cells to influence spermatogenesis and steroidogenesis respectively. Indeed, the leukemia inhibitory factor receptor (LIFR) is expressed in germ cells, Sertoli cells, Leydig cells, PTM cells and testicular macrophages, suggesting that LIF signalling via LIFR may be a key paracrine regulator of testicular function. However, a precise role(s) for testicular LIFR-signalling in vivo has not been established. To this end, we generated and characterised the testicular phenotype of mice lacking LIFR either in germ cells, Sertoli cells or both, to identify a role for LIFR-signalling in testicular development/function. Our analyses reveal that LIFR is dispensable in germ cells for normal spermatogenesis. However, Sertoli cell LIFR ablation results in a degenerative phenotype, characterised by abnormal germ cell loss, sperm stasis, seminiferous tubule distention and subsequent atrophy of the seminiferous tubules.


Assuntos
Subunidade alfa de Receptor de Fator Inibidor de Leucemia/metabolismo , Células de Sertoli/metabolismo , Espermatogênese , Testículo/fisiologia , Animais , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/deficiência , Masculino , Camundongos , Camundongos Knockout
13.
Mol Ther ; 26(7): 1669-1684, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29703701

RESUMO

Pluripotent stem cell-derived differentiated endothelial cells offer high potential in regenerative medicine in the cardiovascular system. With the aim of translating the use of a human stem cell-derived endothelial cell product (hESC-ECP) for treatment of critical limb ischemia (CLI) in man, we report a good manufacturing practice (GMP)-compatible protocol and detailed cell tracking and efficacy data in multiple preclinical models. The clinical-grade cell line RC11 was used to generate hESC-ECP, which was identified as mostly endothelial (60% CD31+/CD144+), with the remainder of the subset expressing various pericyte/mesenchymal stem cell markers. Cell tracking using MRI, PET, and qPCR in a murine model of limb ischemia demonstrated that hESC-ECP was detectable up to day 7 following injection. Efficacy in several murine models of limb ischemia (immunocompromised/immunocompetent mice and mice with either type I/II diabetes mellitus) demonstrated significantly increased blood perfusion and capillary density. Overall, we demonstrate a GMP-compatible hESC-ECP that improved ischemic limb perfusion and increased local angiogenesis without engraftment, paving the way for translation of this therapy.


Assuntos
Células Endoteliais/citologia , Membro Posterior/citologia , Isquemia/terapia , Neovascularização Fisiológica/fisiologia , Animais , Biomarcadores/metabolismo , Diferenciação Celular/fisiologia , Linhagem Celular , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Células Endoteliais/metabolismo , Membro Posterior/metabolismo , Humanos , Isquemia/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Pericitos/citologia , Pericitos/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Transplante de Células-Tronco/métodos
14.
Mol Cell Endocrinol ; 465: 82-91, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29024781

RESUMO

Male disadvantage in cardiovascular health is well recognised. However, the influence of androgens on atherosclerosis, one of the major causes of many life-threatening cardiovascular events, is not well understood. With the dramatic increase in clinical prescription of testosterone in the past decade, concerns about the cardiovascular side-effects of androgen supplementation or androgen deprivation therapy are increasing. Potential atheroprotective effects of testosterone could be secondary to (aromatase-mediated) conversion into oestradiol or, alternatively, to direct activation of androgen receptors (AR). Recent development of animal models with cell-specific AR knockout has indicated a complex role for androgen action in atherosclerosis. Most studies suggest androgens are atheroprotective but the precise role of AR remains unclear. Increased use of AR knockout models should clarify the role of AR in atherogenesis and, thus, lead to exploitation of this pathway as a therapeutic target.


Assuntos
Aterosclerose/metabolismo , Receptores Androgênicos/metabolismo , Animais , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Modelos Animais de Doenças , Humanos , Neointima/metabolismo , Neointima/patologia , Neovascularização Fisiológica , Remodelação Vascular
16.
Sci Rep ; 7(1): 10633, 2017 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-28878267

RESUMO

Carbonyl Reductase 1 (CBR1) is a ubiquitously expressed cytosolic enzyme important in exogenous drug metabolism but the physiological function of which is unknown. Here, we describe a role for CBR1 in metabolism of glucocorticoids. CBR1 catalyzes the NADPH- dependent production of 20ß-dihydrocortisol (20ß-DHF) from cortisol. CBR1 provides the major route of cortisol metabolism in horses and is up-regulated in adipose tissue in obesity in horses, humans and mice. We demonstrate that 20ß-DHF is a weak endogenous agonist of the human glucocorticoid receptor (GR). Pharmacological inhibition of CBR1 in diet-induced obesity in mice results in more marked glucose intolerance with evidence for enhanced hepatic GR signaling. These findings suggest that CBR1 generating 20ß-dihydrocortisol is a novel pathway modulating GR activation and providing enzymatic protection against excessive GR activation in obesity.


Assuntos
Carbonil Redutase (NADPH)/metabolismo , Metabolismo Energético , Glucocorticoides/metabolismo , Obesidade/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Carbonil Redutase (NADPH)/genética , Modelos Animais de Doenças , Feminino , Expressão Gênica , Estudos de Associação Genética , Variação Genética , Glucocorticoides/química , Glucocorticoides/urina , Cavalos , Humanos , Hidrocortisona/metabolismo , Hidroxicorticosteroides/metabolismo , Hidroxicorticosteroides/urina , Fígado/metabolismo , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Obesidade/genética , Fenótipo , Ligação Proteica , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/química , Relação Estrutura-Atividade
17.
J Endocrinol ; 234(3): 291-299, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28676523

RESUMO

11ß-Hydroxysteroid dehydrogenase-1 (11ß-HSD1) predominantly converts inert glucocorticoids into active forms, thereby contributing to intracellular glucocorticoid levels. 11ß-HSD1 is dynamically regulated during inflammation, including in macrophages where it regulates phagocytic capacity. The resolution of inflammation in some disease models including inflammatory arthritis is impaired by 11ß-HSD1 deficiency or inhibition. However, 11ß-HSD1 deficiency/inhibition also promotes angiogenesis, which is beneficial in mouse models of surgical wound healing, myocardial infarction or obesity. The cell types responsible for the anti-inflammatory and anti-angiogenic roles of 11ß-HSD1 have not been characterised. Here, we generated Hsd11b1MKO mice with LysM-Cre mediated deletion of Hsd11b1 to investigate whether 11ß-HSD1 deficiency in myeloid phagocytes is pro-angiogenic and/or affects the resolution of inflammation. Resolution of inflammatory K/BxN-induced arthritis was impaired in Hsd11b1MKO mice to a similar extent as in mice globally deficient in 11ß-HSD1. This was associated with >2-fold elevation in levels of the endothelial marker Cdh5 mRNA, suggesting increased angiogenesis in joints of Hsd11b1MKO mice following arthritis. A pro-angiogenic phenotype was confirmed by measuring angiogenesis in subcutaneously implanted polyurethane sponges, in which Hsd11b1MKO mice showed 20% greater vessel density than their littermate controls, associated with higher expression of Cdh5 Thus, 11ß-HSD1 deficiency in myeloid phagocytes promotes angiogenesis. Targeting 11ß-HSD1 in macrophages may be beneficial in tissue repair.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/deficiência , Inflamação/enzimologia , Macrófagos/enzimologia , Neovascularização Patológica/enzimologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/imunologia , Animais , Humanos , Inflamação/genética , Inflamação/imunologia , Macrófagos/imunologia , Camundongos , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia
18.
ACS Nano ; 11(5): 4542-4552, 2017 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-28443337

RESUMO

The development of engineered nanomaterials is growing exponentially, despite concerns over their potential similarities to environmental nanoparticles that are associated with significant cardiorespiratory morbidity and mortality. The mechanisms through which inhalation of nanoparticles could trigger acute cardiovascular events are emerging, but a fundamental unanswered question remains: Do inhaled nanoparticles translocate from the lung in man and directly contribute to the pathogenesis of cardiovascular disease? In complementary clinical and experimental studies, we used gold nanoparticles to evaluate particle translocation, permitting detection by high-resolution inductively coupled mass spectrometry and Raman microscopy. Healthy volunteers were exposed to nanoparticles by acute inhalation, followed by repeated sampling of blood and urine. Gold was detected in the blood and urine within 15 min to 24 h after exposure, and was still present 3 months after exposure. Levels were greater following inhalation of 5 nm (primary diameter) particles compared to 30 nm particles. Studies in mice demonstrated the accumulation in the blood and liver following pulmonary exposure to a broader size range of gold nanoparticles (2-200 nm primary diameter), with translocation markedly greater for particles <10 nm diameter. Gold nanoparticles preferentially accumulated in inflammation-rich vascular lesions of fat-fed apolipoproteinE-deficient mice. Furthermore, following inhalation, gold particles could be detected in surgical specimens of carotid artery disease from patients at risk of stroke. Translocation of inhaled nanoparticles into the systemic circulation and accumulation at sites of vascular inflammation provides a direct mechanism that can explain the link between environmental nanoparticles and cardiovascular disease and has major implications for risk management in the use of engineered nanomaterials.


Assuntos
Nanopartículas Metálicas/administração & dosagem , Doenças Vasculares/metabolismo , Administração por Inalação , Adulto , Animais , Ouro , Voluntários Saudáveis , Humanos , Pulmão/patologia , Masculino , Camundongos , Nanopartículas , Nanoestruturas/análise , Tamanho da Partícula , Doenças Vasculares/terapia
19.
PLoS Med ; 14(2): e1002248, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28245243

RESUMO

BACKGROUND: Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension. METHODS AND FINDINGS: To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 µg/kg/d and then 60 min at 30 µg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study's main limitations were the relatively small sample size and stable, well-compensated population. CONCLUSIONS: Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required. TRIAL REGISTRATION: ClinicalTrials.gov NCT01640964.


Assuntos
Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Relaxina/farmacologia , Relaxina/uso terapêutico , Adolescente , Adulto , Idoso , Animais , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Rim/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Fluxo Sanguíneo Regional/efeitos dos fármacos , Escócia , Adulto Jovem
20.
Sci Rep ; 7: 44233, 2017 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-28287126

RESUMO

Assessing the retention of cell therapies following implantation is vital and often achieved by labelling cells with 2'-[18F]-fluoro-2'-deoxy-D-glucose (18F-FDG). However, this approach is limited by local retention of cell-effluxed radiotracer. Here, in a preclinical model of critical limb ischemia, we assessed a novel method of cell tracking using 3'-deoxy-3'-L-[18F]-fluorothymidine (18F-FLT); a clinically available radiotracer which we hypothesise will result in minimal local radiotracer reuptake and allow a more accurate estimation of cell retention. Human endothelial cells (HUVECs) were incubated with 18F-FDG or 18F-FLT and cell characteristics were evaluated. Dynamic positron emission tomography (PET) images were acquired post-injection of free 18F-FDG/18F-FLT or 18F-FDG/18F-FLT-labelled HUVECs, following the surgical induction of mouse hind-limb ischemia. In vitro, radiotracer incorporation and efflux was similar with no effect on cell viability, function or proliferation under optimised conditions (5 MBq/mL, 60 min). Injection of free radiotracer demonstrated a faster clearance of 18F-FLT from the injection site vs. 18F-FDG (p ≤ 0.001), indicating local cellular uptake. Using 18F-FLT-labelling, estimation of HUVEC retention within the engraftment site 4 hr post-administration was 24.5 ± 3.2%. PET cell tracking using 18F-FLT labelling is an improved approach vs. 18F-FDG as it is not susceptible to local host cell reuptake, resulting in a more accurate estimation of cell retention.


Assuntos
Rastreamento de Células/métodos , Didesoxinucleosídeos , Células Endoteliais da Veia Umbilical Humana/citologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Didesoxinucleosídeos/farmacocinética , Didesoxinucleosídeos/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Traçadores Radioativos
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