microfibrilas e trombose
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Microfibrilas e Trombose. Cl áudio C. Werneck Departamento de Bioquímica-IB UNICAMP. Fibras Elásticas em Tecidos em Desenvolvimento. Davis E.C. Proteínas Componentes das Microfibrilas Associadas à Elastina. Fibrilina 1 Fibrilina 2 LTBP 2. MP70/78 (big-H3). MAGP-1 MAGP-2. - PowerPoint PPT PresentationTRANSCRIPT
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Microfibrilas e Trombose
Cláudio C. Werneck
Departamento de Bioquímica-IB
UNICAMP
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Fibras Elásticas em Tecidos em Desenvolvimento
Davis E.C. Davis E.C.
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Proteínas Componentes das Microfibrilas Associadas à Elastina
•Fibrilina 1Fibrilina 1•Fibrilina 2Fibrilina 2•LTBP 2LTBP 2
•MP70/78 (big-H3)MP70/78 (big-H3)
•MAGP-1MAGP-1•MAGP-2MAGP-2
Gibson et al. Gibson et al. J. Biol. Chem. 1989, 264J. Biol. Chem. 1989, 264:4590:4590
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Artéria carótida
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A região carboxi-terminal da MAGP-2 interage com diferentes proteínas
Clone Identity of isolated clones8 Fibrillin-11 Fibrillin-23 Fibrillin-25 Fibrillin-230 Fibrillin-29 Fibulin-17 Jagged-115 MEGF-66 Von Willebrand factor21 Glycogenin10 HMG144 Unknown29 Unknown Penner et al. J. Biol. Chem. 2002,
277:35044.
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Função do Fator de von Willebrand na Agregação Plaquetária
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Aplicação do laser 540 nm
3
Posicionamento da ultra-sonda
2
Modelo de Lesão da Artéria Carótida
Isolamento do vaso
1
Injeção do corante
4
Medida do tempo de oclusão
5
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Modelo de Trombose da Artéria Carótida
Time (min)20 40 6010 30 500
0.5
1.0
0.0
Rose Bengal IV Occlusion Time
Blood flow(ml/min)
-10
Laser on
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Camundongos Deficientes em MAGP1 Apresentam Tempo de Oclusão Prolongado
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A Injeção de MAGP1 Recombinante Resgata o Tempo de Oclusão Normal
Werneck et al., BLOOD, 2008, 111: 4137.
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Pull down com Proteínas Plasmáticas
FN Fbg vWF
Werneck et al., BLOOD, 2008, 111: 4137.
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Werneck et al., BLOOD, 2008, 111: 4137.
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Possíveis Funções da MAGP-1 na Agregação de Plaquetas
MAGP-1 MAGP-1
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MRAASLFLLF LPAFLLAQGQ YDLDPLPPYP DHVQYTHYSE QIENPDYYDY PEMTPRPPEE QFQFQSQQQV QQEVIPAPTL EPGTVETEPT EPGPLDCREE
QYPCTRLYSI HKPCKQCLNE VCFYSLRRVY VVNKEICVRT
VCAQEELLRA DLCRDKFSKC GVLASSGLCQ SVAAACARSC GGC
MAGP-1
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A região carboxi-terminal da MAGP1 apresenta
atividade pró-trombótica
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DCREE QYPCTRLYSI HKPCKQCLNE VCFYSLRRVY VVNKEICVRT
VCAQEELLRA DLCRDKFSKC GVLASSGLCQ SVAAACARSC GGC
MAGP-1
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TSP-1 Peptide
• Thrombospondin-1: KRFYVVMWKK
• MAGP-1: RRVYVVNK
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Model for TSP1 in platelet-platelet interactions
Bonnefoy et al., Cell. Mol. Life Sci. 2008
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Bone phenotypes in MAGP1 -/- mice
WEINBAUM et al., J. B. C., 2008.
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WEINBAUM et al., J. B. C., 2008.
Bone phenotypes in MAGP1 -/- mice
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Active Forms of BMP-7 and TGF-β1 Bind to MAGP1
WEINBAUM et al., J. B. C., 2008.
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Estrutura dos Domínios nas Famílias das Fibrilinas e LTBPs.
RGD
Pro
RGD RGD
Gly
RGD
EGFEGF--Ca2+ Binding
8-Cys (CCC)
Hybrid (CC)
Unique
Glycosylation (potential)
Unknown
RGD
Fibrilina-1
Fibrilina-2
LTBP-1
LTBP-2
LTBP-3
LTBP-4
RGD
RGD RGD
G/PFibrilina-3
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Síndrome de Marfan
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Nature Genetics 33:406 (2003)
Fbn1mgΔ (inframe hypomorphic deletion)
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Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome
Jennifer P. Habashi,1* Daniel P. Judge,2* Tammy M. Holm,1 Ronald D. Cohn,1 Bart L. Loeys,1Timothy K. Cooper,1,3 Loretha Myers,1 Erin C. Klein,1 Guosheng Liu,3 Carla Calvi,2Megan Podowski,2 Enid R. Neptune,2 Marc K. Halushka,4 Djahida Bedja,3Kathleen Gabrielson,3 Daniel B. Rifkin,5 Luca Carta,6 Francesco Ramirez,6David L. Huso,3 Harry C. Dietz1,2†
Science 312, 117 (2006)
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Tempo de oclusão x Losartan
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Tratamento com Atenolol e Captopril
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AgradecimentosUNICAMPCristina P. Vicente Paulo P. Joazeiro Denise Machado Tallita VassequiAna Claudia C. N. Diez João Batista Fabrin NetoCatherine Pereira Silvio ConsonniTalita Dellariva Guilherme BragaFabiana Uno de Souza Danielle SousaWashington University in Saint Louis-MOBob Mecham Tom BroekelmannDoug Tollefsen
São Paulo J. E. Krieger Lygia V. PereiraLeonardo dos Santos