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Caractérisation de BMP9 (Bone Morphogenetic Protein 9), un nouveau biomarqueur de l'angiogenèse ? / Charactérization of BMP9, a new angiogenesis biomarker?Bidart, Marie 11 October 2012 (has links)
Les Bone Morphogenetic Proteins (BMP) jouent un rôle important dans de nombreux processus physiopathologiques, en particulier dans les processus d'angiogenèse. La mise au point de méthodes de détection sensibles et spécifiques pourrait être utiles pour des applications cliniques potentielles. Ce travail s'intéresse à BMP9, molécule récemment identifiée par notre équipe comme le ligand physiologique et spécifique du récepteur orphelin Activin Receptor-Like Kinase 1 (ALK1). BMP9 est présent dans le sang et joue un rôle de facteur de quiescence de l'endothélium vasculaire. Ces observations nous ont permis de proposer que la concentration sanguine de BMP9 pourrait être un marqueur de l'état d'activation de l'endothélium vasculaire. Afin de valider cette hypothèse, trois objectifs ont été définis : 1/ mettre au point une méthode de dosage sensible et spécifique de BMP9 circulant, 2/ caractériser les sites d'expression et les formes circulantes de BMP9 et 3/ évaluer la pertinence de BMP9 comme biomarqueur de l'angiogenèse physiologique et pathologique, en particulier tumorale. La première partie de mon travail de thèse a consisté à développer deux méthodes de dosage. La première consiste en une méthode biologique, basé sur l'utilisation d'un gène rapporteur sous le contrôle du promoteur BRE (BMP Responsive Element) qui répond à l'activation de la voie des BMPs. La seconde méthode est basée sur un système « sandwich » de type immunoenzymatique. Les caractéristiques de ces méthodes ont été établies. Dans un second temps, grâce à ces outils, nous avons montré que BMP9 est une protéine produite principalement par les hépatocytes et qu'elle circule majoritairement sous une forme active, complexée à son pro-domaine. Une forme inactive homo-dimérique non clivée est aussi synthétisée. Ce travail confirme également le rôle de BMP9 dans la quiescence de l'endothélium vasculaire. Dans la dernière partie de ce travail, le taux de BMP9 a été mesuré dans des fluides biologiques de patient(e)s présentant diverses situations physiopathologiques. Une augmentation de la concentration sanguine de BMP9 est observée peu de temps avant l'accouchement ; chez les patientes pré-éclamptiques des taux plus élevés de BMP9 sont aussi observés, ouvrant des perspectives dans le domaine obstétrical. Dans les pathologies tumorales, nos observations montrent que BMP9 n'a pas d'intérêt en tant que marqueur diagnostique ou pronostique. Toutefois, les données recueillies dans le cancer médullaire de la thyroïde traité par vandétanib suggèrent que la mesure du taux de BMP9 circulant pourrait avoir une valeur prédictive sur l'efficacité du traitement. Ainsi, l'utilisation du dosage de BMP9 comme marqueur prédictif ou pharmacodynamique des thérapies anti-angiogéniques doit être envisagé. En effet, à l'heure actuelle, l'index thérapeutique des traitements anti-angiogéniques pourrait être amélioré s'il était possible d'identifier et de valider des biomarqueurs susceptibles de prédire précocement l'efficacité clinique ou le développement de résistances au traitement. Cette perspective apparait d'autant plus intéressante que deux molécules, ciblant la voie de signalisation Alk1 ont récemment été développées et présentent des résultats prometteurs, en particulier chez les patients présentant une résistance aux anti-VEGF. / The Bone Morphogenetic Proteins (BMPs) play an important role in many pathophysiological processes, particularly in angiogenesis. The development of sensitive and specific detection methods could be useful for potential clinical applications. This work focuses on BMP9, a molecule recently identified by our team as the physiological and specific ligand of the orphan receptor Activin Receptor-Like Kinase 1 (ALK1). BMP9 is a circulating vascular quiescence factor. These observations have allowed us to propose that BMP9 blood concentration could be a biomarker of the activation state of the vascular endothelium. To validate this hypothesis, three objectives were defined: 1 / Develop a sensitive and specific assay of circulating BMP9, 2 / characterize expression sites and circulating forms of BMP9 and 3 / evaluate the relevance of BMP9 as a biomarker for physiological and pathological angiogenesis, in particular tumor. The first part of my thesis was to develop two assays. The first is a biological method, based on the use of a reporter gene under the control of the promoter BMP Responsive Element (BRE) which responds to the activation of the BMPs. The second method is based on a "sandwich"-type immunoassay. The characteristics of these methods have been established. In a second step, using these tools, we have shown that BMP9 is a protein produced mainly by hepatocytes and circulates predominantly in an active form complexed to its pro-domain. An inactive form homo-dimeric uncleaved is also synthesized. This work also confirms the role of BMP9 in the quiescence of vascular endothelium. In the last part of this work, the rate of BMP9 was measured in biological fluids of the patient (s) with various pathophysiological situations. An increase in the blood concentration of BMP9 is observed shortly before delivery and in preeclamptic patients higher rates of BMP9 were also observed, opening perspectives in obstetrics. In tumoral pathology, our observations show that BMP9 has no value as diagnostic or prognostic marker. However, the data collected in medullary carcinoma of the thyroid treated by vandetanib suggest that the measurement of circulating BMP9 rates could have a predictive value for the efficacy of treatment. So, the use of the BMP9 assay as a predictive marker or pharmacodynamic marker of anti-angiogenic therapies should be considered. Indeed, at present, the therapeutic index of anti-angiogenic treatments could be improved if it were possible to identify and validate biomarkers that may predict early clinical efficacy or the development of resistance to treatment. This perspective appears particularly interesting since two molecules targeting the signaling pathway Alk1 have recently been developed and show promising results, especially in patients with resistance to anti-VEGF
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Efeito agudo do inibidor da fosfodiesterase tipo 5 (sildenafil) na pressão sanguínea arterial durante e após exercício em pacientes submetidos a transplante cardíaco / Acute effects of a single dose of phosphodiesterase type 5 inhibitor (sildenafil) on systemic arterial blood pressure during and after exercise in heart transplant recipients.Garlipp, Veridiana Moraes D'Avila Damas 11 June 2008 (has links)
Introdução: A hipertensão arterial sistêmica (HA) pode estar associada à diminuição na produção e liberação do óxido nítrico derivado do endotélio (NO). O uso do sildenafil leva ao aumento de monofosfato de guanosina cíclica (GMPc), um importante mediador de NO. Contudo, pouco se sabe sobre os efeitos da inibição da fosfodiesterase tipo 5 (PDE5) na monitorização da pressão arterial 24-h (MAPA), pressão arterial durante exercício, noraepinefrina (Nor) e capacidade ao exercício, principalmente após transplante de coração (TX). Métodos: Nós estudamos 22 pacientes pós TX, os quais foram randomizados, tomando dose única de sildenafil (50mg) ou placebo (50mg), aproximadamente uma hora antes de iniciar o protocolo. No dia 1, os pacientes realizaram avaliação clínica, teste cardiopulmonar de caminhada de seis minutos (TES) seguido de teste de esforço cardiopulmonar (TE), Após o término dos testes em esteira, foi colocado o MAPA. Determinamos em repouso (rep), último minuto do TES (6) e pico do TE (Ex): FC (bpm) PAS e PAD (mmHg), VO2(ml/kg/min), Slope VE/VCO2, tempo de exercício (TE, min), distância (TES, Km) e Nor (pg/ml). No dia 2 o protocolo foi repetido, realizando-se o cross-over. Dezessete pacientes apresentavam HA. Resultados: (Pl e Sil respectivamente), Sil reduziu (p<0.05): PAS-rep(138±7 vs 122±18); PAD-rep(83±12 vs 78±12); PAS-6(156± 20 vs 137± 22); PAD-6(82±13 vs 77±14); PAS-Ex(155± 27vs 124±36); PAD-Ex(79±16 vs 66± 16); PAS 24-h(121±10 vs 114±9), PAD 24-h(80±6 vs 76±5), PAS vigília(122±11 vs 115±9), PAD vigília(81± 6 vs 76±5) e PAS noturna(119±12 vs 112±10), PAD noturna(78±7 vs 73±8); e aumentou Nor-repouso(483±165 vs 622±211). Sil não alterou rep, 6 e EX: FC, VO2 e Slope. Conclusão: O ciclo NO-cGMP parece desempenhar papel importante no controle da pressão arterial em TX. Sendo que, a inibição da PDE5 parece apresentar efeitos benéficos no controle da hipertensão arterial em TX, podendo ser utilizada concomitantemente a terapia anti-hipertensiva usual. / Background: Systemic hypertension (SH) can be associated with a decrease in endothelium-dependent nitric oxide (NO). Sildenafil determines increment in cyclic guanosine monophosphate (cGMP) that a mediator of NO. However, little is known about the effects of PDE5 inhibition on 24-hour ambulatory (ABP) and exercise blood pressure, noreprinephrine (Nor) and exercise capacity, specially after heart transplantation (HT). Methods: We studied 22 HT pts that on the 1st day underwent a cardiopulmonary (CP) self-controlled treadmill 6walk test(6) and, after, an ECG monitored CP treadmill maximal exercise test(Ex) within 60 and 90 min after oral Sildenafil (Sil,50mg) or placebo(Pl) given at random, and ABP. We determined at basal position(b), last min of 6 and the peak Ex the HR(bpm), SBP and DBP (mmHg), VO2(ml/kg/min), Slope VE/VCO2, exercise time(ET, min), distance(D, Km) and Nor(pg/ml). Also, after CP tests 24-h SBP and DBP were monitored. It was repeated on the 2nd day when the cross-over was done. Seventeen pts had SH. Results: (Pl and Sil respectively), Sil reduced (p<0.05): b- SBP(138±7 vs 122±18); b-DBP(83±12 vs 78±12); 6-SBP(156± 20 vs 137± 22); 6-DBP(82±13 vs 77±14); Ex-SBP(155± 27vs 124±36); Ex-DBP(79±16 vs 66± 16); 24-h SBP(121±10 vs 114±9) and DBP(80±6 vs 76±5), daytime SBP(122±11 vs 115±9) and DBP(81± 6 vs 76±5) and nighttime SBP(119±12 vs 112±10) and DBP(78±7 vs 73±8); and increase b-Nor(483±165 vs 622±211). Sil did not change in b, 6 and EX; HR, Nor, VO2 and Slope. Conclusion: NO-cGMP pathway seems to play a role in blood pressure control in HT. The PDE5 inhibition could have potential beneficial effects on hypertensive HT in addition to antihypertensive therapy.
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Efeito agudo do inibidor da fosfodiesterase tipo 5 (sildenafil) na pressão sanguínea arterial durante e após exercício em pacientes submetidos a transplante cardíaco / Acute effects of a single dose of phosphodiesterase type 5 inhibitor (sildenafil) on systemic arterial blood pressure during and after exercise in heart transplant recipients.Veridiana Moraes D'Avila Damas Garlipp 11 June 2008 (has links)
Introdução: A hipertensão arterial sistêmica (HA) pode estar associada à diminuição na produção e liberação do óxido nítrico derivado do endotélio (NO). O uso do sildenafil leva ao aumento de monofosfato de guanosina cíclica (GMPc), um importante mediador de NO. Contudo, pouco se sabe sobre os efeitos da inibição da fosfodiesterase tipo 5 (PDE5) na monitorização da pressão arterial 24-h (MAPA), pressão arterial durante exercício, noraepinefrina (Nor) e capacidade ao exercício, principalmente após transplante de coração (TX). Métodos: Nós estudamos 22 pacientes pós TX, os quais foram randomizados, tomando dose única de sildenafil (50mg) ou placebo (50mg), aproximadamente uma hora antes de iniciar o protocolo. No dia 1, os pacientes realizaram avaliação clínica, teste cardiopulmonar de caminhada de seis minutos (TES) seguido de teste de esforço cardiopulmonar (TE), Após o término dos testes em esteira, foi colocado o MAPA. Determinamos em repouso (rep), último minuto do TES (6) e pico do TE (Ex): FC (bpm) PAS e PAD (mmHg), VO2(ml/kg/min), Slope VE/VCO2, tempo de exercício (TE, min), distância (TES, Km) e Nor (pg/ml). No dia 2 o protocolo foi repetido, realizando-se o cross-over. Dezessete pacientes apresentavam HA. Resultados: (Pl e Sil respectivamente), Sil reduziu (p<0.05): PAS-rep(138±7 vs 122±18); PAD-rep(83±12 vs 78±12); PAS-6(156± 20 vs 137± 22); PAD-6(82±13 vs 77±14); PAS-Ex(155± 27vs 124±36); PAD-Ex(79±16 vs 66± 16); PAS 24-h(121±10 vs 114±9), PAD 24-h(80±6 vs 76±5), PAS vigília(122±11 vs 115±9), PAD vigília(81± 6 vs 76±5) e PAS noturna(119±12 vs 112±10), PAD noturna(78±7 vs 73±8); e aumentou Nor-repouso(483±165 vs 622±211). Sil não alterou rep, 6 e EX: FC, VO2 e Slope. Conclusão: O ciclo NO-cGMP parece desempenhar papel importante no controle da pressão arterial em TX. Sendo que, a inibição da PDE5 parece apresentar efeitos benéficos no controle da hipertensão arterial em TX, podendo ser utilizada concomitantemente a terapia anti-hipertensiva usual. / Background: Systemic hypertension (SH) can be associated with a decrease in endothelium-dependent nitric oxide (NO). Sildenafil determines increment in cyclic guanosine monophosphate (cGMP) that a mediator of NO. However, little is known about the effects of PDE5 inhibition on 24-hour ambulatory (ABP) and exercise blood pressure, noreprinephrine (Nor) and exercise capacity, specially after heart transplantation (HT). Methods: We studied 22 HT pts that on the 1st day underwent a cardiopulmonary (CP) self-controlled treadmill 6walk test(6) and, after, an ECG monitored CP treadmill maximal exercise test(Ex) within 60 and 90 min after oral Sildenafil (Sil,50mg) or placebo(Pl) given at random, and ABP. We determined at basal position(b), last min of 6 and the peak Ex the HR(bpm), SBP and DBP (mmHg), VO2(ml/kg/min), Slope VE/VCO2, exercise time(ET, min), distance(D, Km) and Nor(pg/ml). Also, after CP tests 24-h SBP and DBP were monitored. It was repeated on the 2nd day when the cross-over was done. Seventeen pts had SH. Results: (Pl and Sil respectively), Sil reduced (p<0.05): b- SBP(138±7 vs 122±18); b-DBP(83±12 vs 78±12); 6-SBP(156± 20 vs 137± 22); 6-DBP(82±13 vs 77±14); Ex-SBP(155± 27vs 124±36); Ex-DBP(79±16 vs 66± 16); 24-h SBP(121±10 vs 114±9) and DBP(80±6 vs 76±5), daytime SBP(122±11 vs 115±9) and DBP(81± 6 vs 76±5) and nighttime SBP(119±12 vs 112±10) and DBP(78±7 vs 73±8); and increase b-Nor(483±165 vs 622±211). Sil did not change in b, 6 and EX; HR, Nor, VO2 and Slope. Conclusion: NO-cGMP pathway seems to play a role in blood pressure control in HT. The PDE5 inhibition could have potential beneficial effects on hypertensive HT in addition to antihypertensive therapy.
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