nemoci-sympt/METABOLISMUS/marfanuv-syndrom/biochemie

Kolageny

COL1A1 gene mutation

• 1 family with atypycal Marfan. syndr.
• X alpha-2 gene of type I collagen [14]
• X alpha-1 chain of type I procollagen [14]
• X collagen crosslinking
• Mělo by smysl klást vyšší důraz na dostatek vitamínu C ? Mno, rozhodně by neměl chybět...
• X hyaluronic acid synthesis
• Cell-free extracts of Marfan fibroblasts had 3 to 10 times more hyaluronic acid synthetase activity than did preparations from normal fibroblasts [14]
• Mělo by smysl užívat k. hyaluronovou v potravních doplňcích ?
• Fibroblasts accumulated collagen-specific tritium-labeled hydroxyproline [14]

Marfan. syndr. a nálezy v aortě a na chlopních

• Reduced desmosine [14]
• Reduced isodesmosine cca o 1/2 [14]
• Jak stimulovat vyšší syntézu / potlačit odbourávání ?

Elastin

• Concentration of elastin per mg dry weight was reduced [14]
• Hydroxyproline content of elastin was increased in 2
• Alkali treatment solubilized 46.2% of an elastin preparation in Marfan aortas compared with 23.7% of controls [14]
• Increase in lysyl residues [14]

Metaloproteinázy

• MMP2 and MMP9 are upregulated during thoracic aortic aneurysm formation in Marfan syndrome
• Elastic fiber degeneration [14]
• Deterioration of aortic contraction [14]
• X mechanical properties of AO [14]
• Neexistují již nějaké nové léky na bázi blokátorů metaloproteináz pro terapii osteoartrozy či revmatické artritidy ?

Erk1/2

• inhibition of Erk1/2 activation ameliorated aortic growth [14]
• To byl ten Losartan. Co dalšího by to umělo?

Smad4

• Smad4 deficiency exacerbated aortic disease and caused premature death in Marfan. syndr. mice [14]
• Activation of Jnk1
• Jnk antagonist ameliorated aortic growth in Marfan mice [14]

Angiotensin receptor 2 - AT2R

• Ztráta expresse accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan. syndr. [14]
• Co stimuluje AT2R expresi ?

Selective AT1 receptor blocker (ARB) losartan

• Abrogated aneurysm progression in the mice
• Full protection required intact AT2 signaling [14]
• ACEI enalapril was less effective
• Limits signaling through both receptors AT1 i AT2 [14]

Haploinsufficiency FBN1

• Triggers secondary cellular events
• Intimal hyperplasia [1]
• Adventitial inflammation [1]
• Protizánětlivá terapie nespecificky je něco vhodné ? Mají nějaký profit z NAF užívaných třbea na bolesti ?
• TGF beta involvement [1]

TGF-beta

• V. s. a mediator of myxomatous mitral valve disease [11]
• Souvisí to s vyšším podílem hydroxyprolinu v elastinu ?

Extracelulární matrix

TGF beta

• Growth factor that regulates cell proliferation
• Migration
• Differentiation
• Cell survival
• TGF beta binds to TGF beta RI and II heterodimers
• Phosphorylation of TGF beta RI
• Phosphorylates signaling proteins Smad2 and Smad3
• Allows association with Smad4
• Nuclear translocation
• Specific gene activation or repression [1]
• Secreted from cells:
• small latent complex (SLC):
• Latency-associated propeptide (LAP)
• Active TGF beta
• large latent complex (LLC):
• SLC
• Latent TGF beta binding protein (LTBP)
• LTBP-1, LTBP-3 bind TGF beta strongly
• LTBP-1 bind in vitro fibrillin-1 = associated of microfibrils [1]
• LLC + fibrillin microfibrils = growth factor highway in tissues [1]

Autoantibodies to a fibrillin-1 proline-rich region

• Release sequestered TGF beta 1 from microfibrils
• Induce fibroblast activation [1]

BMP-1

• Controls TGF beta 1 activation
• Cleaving LTBP-1 [1]

TSP-1

• Physiological activator of TGF beta [1]
• Competitive binding of a TSP-1 sequence (KRFK) that releases TGFß from SLC [1]
• S čím soutěží o tu vazbu? Jak se dá potlačit?
• Fragmenty fibrillinu 1 silnější aktivátory [1]
• Prevence vzniku další fragmentace fibrilinu...

Integrin

• Aktivace TGF beta

Proteolysis

• Aktivace TGF beta

Syndecan-4

• Aktivace TGF beta [1]

Literatura: