MMP: nimiluettelo ja substraatit. TIMP: nimiluettelo ja tehtävät

The Matrix Metalloproteinase (MMP) and Tissue Inhibitor of Metalloproteinase (TIMP) GenesMatrix Metalloproteinase Protocols, Volume 151: 5Vincenti, Matthew P.Springer Protocols – Jan 1, 2001

Developmental and homeostatic remodeling of the extracellular matrix (ECM) is a highly regulated process orchestrated by a family of zinc-containing, calcium-dependent neutral proteases known as the matrix metallo-proteinases (MMP). This family of enzymes, which now contains twenty members, can collectively degrade all structural proteins of the ECM including interstitial collagens (I, II, III, and V), basement membrane collagens (IV), fibronectin, laminin, proteoglycan, and elastin ( Table 1 ).

The enzymatic activity of MMP family members is controlled by a group of inhibitor proteins known as the Tissue Inhibitors of Metalloproteinases (TIMPs), which consist of four family members ( Table 2 ). Whereas all four TIMPs can inhibit all MMPs in vitro, preferential TIMP-MMP interactions and tissue-restricted TIMP expression suggest that each TIMP has a specific function ( Table 2 ).

• Table 1. Matrixmetalloproteinaasit.  The Matrix Metalloproteinases (MMPs) 

  MMP family member

 Common names

 Substrates 

 Selected references

MMP-1 

Collagenase-1

•  Collagens I, II, III, VI, X, gelatins, aggrecan, entactin (154–158)

MMP-2

 72 kDa Gelatinase, Gelatinase A 

• Gelatins, collagens I,IV, V, VII, X, XI, fibronectin, laminin, aggrecan, elastin, large tenascin C, vitronectin, β-amyloid protein precursor (157–159)

MMP-3

 Stromelysin-1

• Aggrecan, gelatins, fibronectin, laminin, collagen III, IV, IX, X, large tenascin C, vitronectin (28,157,158,160,161)

MMP-7

 Matrilysin,

•  Pump Aggrecan, fibronectin, laminin, collagen IV, elastin, entactin, small tenascin C, vitronectin (157,158,162,163)

MMP-8

 Collagenase-2, Neutrophil Collagenase

•  Collagens I, II, III, aggrecan (157,158,164)

MMP-9

 92 kDa Gelatinase, Gelatinase B

•  Gelatins, collagens IV, V, XIV, aggrecan, elastin, entactin, vitronectin (157,158,165,166)

MMP-10

 Stromelysin-2

•  Aggrecan, fibronectin, laminin, collagen IV (157,158,167)

MMP-11

 Stromelysin-3

•  Fibronectin, laminin, collagen IV, aggrecan, gelatins (141,158)

MMP-12 

Metalloelastase

•  Elastin (147,158) MMP-13 Collagenase-3 Collagens I, II, III (88,89,124,158,168,169)

MMP-14

 Membrane-type-1 -MMP

•  Collagens I, II, III, fibronectin, laminin, vitronectin, proteoglycan, ProMMP-2, ProMMP-13 (158,170)

MMP-15

 Membrane-type-2-MMP 

•  Not known (158,171

MMP-16

 Membrane-type-3-MMP

•  ProMMP-2 (158,172)

MMP-17

 Membrane-type-4-MMP

•  Not known (158,173)

MMP-18 

Collagenase-4, Xenopus Collagenase

•  Collagen I (158,174,175)

MMP-19

•  Not Known (158,176,177)

MMP-20   

Enamelysin

•  Amelogenin (The major tooth enamel matrix protein) (178)

Table 2

Matelloproteinaasien kudosestäjät

Tissue Inhibitors of Metalloproteinases (TIMPs)

Family Reported functions Selected References

• TIMP-1

   Inhibition of all known MMP family members. Associates with proMMP-9. Inhibits angiogenesis. Erythroid-potentiating actvity. (179–181)

• TIMP-2 

   Inhibitions of  all known MMP family members. Associates with MT1-MMP and MMP-2 at cell surface and regulates MMP-2 activation. (181–184)

• TIMP-3 

  Inhibition of all known MMP family members. Extracellular matrix-associated. Mutation associated with Sorsby's fundus dystrophy. (55,181,185–188)

• TIMP-4 

  Inhibition of all known MMP family members. Restricted expression suggests tissue specific TIMP function. (181,189,190)

Vaskulaariset gelatinaasit MMP-2 ja MMP-9. Denguen vaarat.

• Nämä ovat sikiökehityksen aikana tärkeät munuaisen verisuoniston muodostumisessa käsittääkseni.

• Kts. Michael Jonssonin väitöskirja: Siinä mainitaan TIMP-1, MMP-9 ja aivokammioiden atrofia valkean aivoaineksen muutosten yhteydessä.  kts. erikseen

MMP-2  nousee  denguetulehduksessa endoteelisolussa ja MMP-9  infektoituneessa dendriittisolussa.
Denguessa on vikana  vaskulaarisen endoteelinen muuttuminen läpäiseväksi jolloin siitä pääse tihkua ulos.

Päivitys 16.4. 2014 . Tätä asiaa  tulee käsitellä enemmän.

LPS säätää ylös uPA, MMP-2 ja MMP-9

Sydänlihassolu kyseessä

 Lipopolysakkaridit (LPS) säätävät ylös uPA, MMP-2 ja MMP-9 geenejä ERK1/2 signalointiteitse sydänlihassolussa.

LÄHDE:
Cheng YC, Chen LM et al. Lipopolysaccharide upregulates uPA, MMP-2 and MMP-9 via ERK1/2 signaling in H9c2 cardiomyoblast cells.

• uPA , tPA, MMP-ryhmän jäsenet säätyvät ylös kun kehittyy sydäninfarkti, dilatoiva kardiomyopatia , sydänfibroosi ja sydäninsuffisienssi.

Upregulation of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and matrix metallopeptidases (MMPs) is associated with the development of myocardial infarction (MI), dilated cardiomyopathy, cardiac fibrosis, and heart failure (HF).

• LPS osallistuu tulehdusvasteeseen kardiovaskulaarisessa järjestelmässä. Mutta ei ole ollut tiedossa, pystyykö LPS säätämään ylös sydänlihassolun geeniexpression tai aktiivisuuden seuraavissa geeneissä ja proteiineissa: uPA, tPA, MMP-2 ja MMP-9

Evidences suggest that lipopolysaccharide (LPS) participates in the inflammatory response in the cardiovascular system; however, it is unknown if LPS is sufficient to upregulate expressions and/or activity of uPA, tPA, MMP-2, and MMP-9 in myocardial cells.

•  Tässä tutkimuksessa käsiteltiin kadiomyoblasteja LPS- materiaalilla, jota saataisiin selville pystyykö se säätämään ylös uPA, tPA, MMP-2 ja MMP-9.  ja edelleen identifioitiin  tarkka molekulaarinen ja solumekanismi, mikä  on ylössaatövasteiden taustalla. 

In this study, we treated H9c2 cardiomyoblasts with LPS to explore whether LPS upregulates uPA, tPA, MMP-2, and MMP-9, and further to identify the precise molecular and cellular mechanisms behind this upregulatory responses. 

•  Tämä tutkimus osoitti, että LPS säätää ylös proteiinit uPA, MMP-2 ja MMP-9 ja indusoi  kadiomyöblastissa  MMP-2 ja MMP-9 metalloproteinaasiaktiivisuutta.

 Here, we show that LPS challenge increased the protein levels of uPA, MMP-2 and MMP-9, and induced the activity of MMP-2 and MMP-9 in H9c2 cardiomyoblasts.

• Kuitenkaan LPS ei osoittanut omaavansa  mitään vaikutusta TIMP-1 , TIMP-2, TIMP-3 ja TIMP-4 tekijöihin, jotka ovat metalloproteinaasien kudosestäjiä.

However, LPS showed no effects on the expression of tissue inhibitor of metalloproteinase-1, -2, -3, and -4 (TIMP-1, -2, -3, and -4).

• Useita inhibiittoreita testattiin LPS materiaalin suhteen:  ERK1/2-nhibiittorin, p38 MAPK inhibiittorin , JNK1/2 inhibiittorin, kalsineuriini-inhibiittorin ja NFkappaB inhibiittorin vaikutusta testattaessa LPS:n aiheuttama ylössäätyminen saatiin estymään vain ensimainitussa  ERK1/2 inhibiittorissa.

After administration of inhibitors including U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor), CsA (calcineurin inhibitor), and QNZ (NFkappaB inhibitor), the LPS-upregulated expression and/or activity of uPA, MMP-2, and MMP-9 in H9c2 cardiomyoblasts are markedly inhibited only by ERK1/2 inhibitors, U0126.

• Yhteenvetona tästä voidaan päätellä että endotoksiini (LPS) säätää ylös uPA, MMP-2 ja MMP-9 aktiivisuudet juuri tämän ERK1/2 signaalitien kautta kardiomyosyytissä.

Collectively, these results suggest that LPS upregulates the expression and/or activity of uPA, MMP-2, and MMP-9 through ERK1/2 signaling pathway in H9c2 cardiomyoblasts.

• Tutkimuksista selviää linkki LPS:n indusoiman sydämen dysfunktion  ja ERK1/2 signalointitien kesken, josta välittyy   uPA, MMP-2 ja MMP-9 ylössäätymiset .

Our findings further provide a link between the LPS-induced cardiac dysfunction and the ERK1/2 signaling pathway that mediates the upregulation of uPA, MMP-2 and MMP-9.

Päivitys 16.4. 2014

Amiloridin vaikutus suoliston suoloihin

C.L. Delgado¹, A. Delgado et al.   Enteral NaCl absorption in normotensive subjects 
 Am J Hypertens (2000) 13 , 156A–157A; doi:S0895-7061(00)00651-8 C003:

Tiivistelmä (Suomennosta), :  Abstract

•  Vaikka usimmissa epiteliaalisissa soluissa on amiloridisensitiivisiä natriumkanavia niin kaikki informaatio amiloridin vaikutuksista perustuu suoliston NaCl absorptioon.

Although amiloride-sensitive Na channels are present in most epithelial cells, any information is available in regard to Amiloride (AI) effects on enteral NaCl absorption.

•  Mainitun vaikutuksen mittaamiseksi tutkijat   määrittivät  elektrolyytit:  plasmasta natriumin, kaliumin, kloridin, jonisoidun kalsiumin,  osmolaalisuuden ;  punasolun Nai ja Ki  sekä  12 tunnin yövirtsasta  natriumin, kaliumin, kloridin, jonisoidun kalsiumin,  osmolaalisuuden  ja pH:n . Tutkimus oli kaksoissokkokoe ja plasebokontrolloitu. Tutkimukseen osallistuneet  matchattiin iän ja sukupuolen mukaan kahteen ryhmään. 

To assess this effect we measured plasma (Na, K, Cl, Ca++ ionized Osmol) RBC (Nai, Ki) and 12-h night urine (Na, K, Cl, Ca++, Osmol, pH) electrolytes, in a double-blind placebo-controlled study, in two age-sex matched groups:A ja B ryhmä. 

Group A (n = 7): 30 1 yr., BMI 25 2 Kg/mt², BP 122 12/77 8 mm Hg vs.

Group B (n = 6): 31 2 yr., BMI 23 3 Kg/mt², BP 116 8/77 5 mm Hg.

•  Kaikki  olivat normaaliravinnolla ja  suolankäyttö oli runsasta . He alkoivat 5 mg amiloriditabletin   yhden viikon käytön (ryhmä A ) tai placebon käytön  ( Ryhmä B).

All on normal diet with large NaCl intake (uNa 145 mmol/l, Cl ; 123 mmol/l, Uosmol,  635 osmol), starting 5 mg AI (Group A)  or placebo (Group B) for 1 week.

• Ennen lääkkeen aloittamista ( 0 päivänä) katsottiin verenpaine, sydämen rytmi, BMI ja plasman, punasolujen ja  yövirtsan elektrolyytit. Sitten koottiin yövirtsa 1-7 päivinä ja kaikki tutkimukset toistettiin 1 viikon wash out jakson jälkeen eli 14. päivä. 

BP, HR, BMI and plasma (Na, K, Cl, Ca++ ionized, Osmol) RBC (Nai, Ki) and 12-h night urine (Na, K, Cl, Ca++, Osmol, pH) electrolytes were obtained before drug (0 day) followed by 12-h urine collection (days 1–7) and all studies repeated after 1 week washout period (day 14).

• Amiloridi oli  laskenut nopeasti virtsan natriumia, kloridia ja virtsan osmolaalisuutta kolmantena päivänä ja  virtsan natriumia ja kloridia sekä virtsan osmolalisuutta  seitsemäntenä päivänä   ja silloin punasolujen  jonisoitu Na oli alentunut plasman natriumin pysytellessä normaalina

AI rapidly decrease uNa 78 19 mmol/l, Cl 86 26 mmol/l and Uosmol 375 109 mosm  at 3rd day and uNa 84 26, Cl 79 21, Uosmol 474 167 at 7th day  with decrease Nai (5 0.2 mmol/lc, p = 0.003) and normal plasma Na.

• Basaalinen virtsan kalium oli laskenut 3. päivänä ja 7. päivänä, mutta jonisoituneen kaliumin ja plasman kaliumin arvoissa ei ollut muutoksia.
•  14. päivänä kaikki plasman ja virtsan elektrolyyttien arvot olivat aiemmilla perustasoillaan. 

Basal uK 38 12 was decreased 21 13 mmol/l at 3rd day (p = 0.002) and 17 4 at 7th day (p.001) without changes in Ki and plasma K. At the 14th day, all plasma and urine electrolytes returned to previous basal levels.

• B-ryhmässä kaikki arvot olivat  placebokokeen aikana entisellään. 

In Group B, all studies were unchanged during placebo trial.

• Tässä tutkijat ovat esittäneet  ensimmäisen näytön amiloridin enteraalisista vaikutuksista, mitkä selittävät  joitan sen farmakologisesta vaikutuksesta. 

We present the first evidence of an enteral effect of AI, which explain some of its pharmacological action.

Avainsanoja,Keywords:

Amiloride, 

NaCl enteral absorption,  Ruokasuolan  suolistoabsorptio (imeytyminen suolesta)

sodium, natrium, Na

potassium, kalium, K

Käännöstä 16.4. 2014

Amiloridi (uPA inhibiittori)

Etsin molekyylejä, joilla voi säädellä matrixmetalloproteinaasien kaskadia. Tänään löysin maininnan siitä, että amiloridi on uPA inhibiittori ja uPA taas voi käynnistää plasmiinin muodostuksen joka saattaa metalloproteinaasimyrskyn aikaan.

LÄHDE:
Xuekang Yang1, Desheng Wang1 et al.
Inhibition of Na+/H+ exchanger 1 by 5-(N-ethyl-N-isopropyl) amiloride reduces hypoxia-induced hepatocellular carcinoma invasion and motility
http://www.cancerletters.info/article/S0304-3835%2810%2900138-2/abstract
Volume 295, Issue 2, Pages 198-204 (28 September 2010)
Received 17 December 2009; received in revised form 26 February 2010; accepted 1 March 2010. published online 25 March 2010.

Tiivistelmä( Suomennosta) Abstract

• Natriumjoni-vetyjoni-vaihtaja 1 (NHE1) omaa merkitsevän osuuden tuumorimetastaasissa.  Kuitenkin  tarkka mekanismi, millä NHE1 välittää soluinvaasiota ja migraatiota varsinkin maksasolukarsinoomassa ei ole vieläkään tiedossa.Tässä tutkimuksessa tiedemiehet osoittavat enimmäistä kertaa, että  5-N-etyyli-N-isopropyyli-amiloridi EEIPA) pystyy  suppressoimaan  maksasyöpäsolun migroitumista ja invasoitumista hypoksiaolosuhteissa. 

Na+/H+ exchanger 1 (NHE1) plays a significant role in tumor metastasis. However, the exact mechanisms by which NHE1 mediates cell invasion and migration, especially in hepatocellular carcinoma (HCC), are not yet known. In the current study, we show for the first time that the inhibition of NHE1 by 5-(N-ethyl-N-isopropyl) amiloride (EIPA) is able to suppress migration and invasion of HepG2 cells under hypoxic conditions.

• Lisäksi hypoksiasa aktivoi ERK 1/2 signaalitien, mikä uolestaan edistää metalloproteinaasien MMP-2 ja MMP-9  sekä vaskulaarisen endoteelin kasvutekijän VEGF tuotantoa. 
• EIPA:n aiheuttaman  suppressoivan roolin  määriteltiin ilmenevän   MMP-2, MMP-9 ja VEGF- alassäätymisinä  ERK1/2 signaalitiestä riippuvalla tavalla.

In addition, hypoxia activated ERK1/2, which in turn promoted the production of MMP-2 , MMP-9 and VEGF. EIPA’s suppressive role was determined to act through down-regulation of MMP-2, MMP-9 and VEGF in an ERK1/2 dependent manner.

•  Saadut tiedot osoittavat, että NHE1 joninvaihtaja omaa osaa maksasolukarsinoman invasoitumisessa ja ettää NHE1 saattaa olla mahdollinen  terapiakohde  maksakarsinooman hoidossa.

The data demonstrate that NHE1 plays a role in HCC invasion and that NHE1 may be a potential therapeutic target for HCC treatment.
Avainsanat, Keywords:
HCC, Hepatocellular carcinoma, maksasolusyöpä
NHE1,  Na+/H+ exchanger 1, natriumjoni-vetyjonivaihtaja 1
 Invasion, invaasio
 Migration, migraatio
 Tumor microenvironment, kasvaimen mikromiljöö
Päivitys 16.4. 2014.

Aortan aneurysmasta

Ruotsin Lääkärilehti kirjoittaa aortan aneurysmasta skånelaisilla miehillä.
Koetan katsoa mikä on MMPs osuus aneurysmissa.

http://www.springerlink.com/content/n332540772578t81/

Abstract(Suomennosta)

Accumulating evidence suggests that abdominal aortic aneurysms (AAA) are due to a pathologic process which results in the destruction of aortic elastin and other matrix components.

On kertyvää näyttöä siitä, että vatsa-aortan aneurysmat johtuvat patologisesta prosessista, joka tuhoaa aortan elastiinia ja muita matrix-komponentteja.

In this study, protein extractions were performed on both aneurysmal and normal aorta.
Tässä tutkittiin aneurysmaattisen ja normaalin aortan proteiiniuutteita.

Extracts were applied to frozen section of normal aorta either alone or in combination with 10 mM ethylenediaminetetraacetic acid, recombinant tissue inhibitor of metalloproteases (rTIMP), 10 mM zinc, and 5 mM phenylmethylsulfonyl fluoride, under conditions where calcium was removed from the buffer.

Katsottiin EDTA:n TIMP-rekombinantin, sinkin ja fenylmetylsulfonylfluoridin estovaikutuksia kalsiumin ollessa poissa.

After incubation, the sections were stained for elastin and evaluated by computerized morphometry.
Inkubaation jälkeen värjättiin elastiini ja sitten arvioitiin morfometrialla.

Aneurysm extracts, only in the presence of calcium, showed significant elastolytic activity characterized by destruction of intact elastic lamellae that was inhibited by ethylenediaminetetraacetic acid (EDTA), the recombinant metalloprotease inhibitor, and zinc.

Vain kalsiumin ollessa läsnä aneurysma-uutteet osoittivat merkitsevää elastolyyttistä aktiivisuutta jota luonnehti ehjän elastisen lamellarakenteen tuhoutuminen. Tämä tuho estyi vain EDTA:lla, rTIMP:lla ja sinkillä.

Phenylmethylsulfonyl fluoride showed no inhibitory activity.
Fenylmetylsulfonylfluoridi ei pystynyt estämään elastisen rakenteen tuhoutumista.

Healthy aortic extract showed no elastolytic activity.
Terveissä aorttauutteissa ei esiintynyt mitään elastolyyttistä aktiivisuutta.

This inhibitory profile is consistent with a metalloenzyme.
Inhibitorinen profiili pitää yhtä metalloentsyymivaikutuksen kanssa.

We conclude that aneurysmal aorta contains elastolytic activity that is secondary to a metalloenzyme which is not present in normal aorta.

Tiedemiehet tekivät johtopäätöksen., että aneurysmaattisessa aortassa on vallalla elastolyyttistä aktiivisuutta, joka on sekundääri-ilmiö sellaiselle metalloentsyymitoiminnalle, mitä ei ole normaaliaortassa

This activity may play a role in the destruction of the elastin matrix that is seen in AAA's.

Tällä aktiivisuudella saattanee olla osuutta siihen elastiinimatriksin tuhoon, mikä nähdään vatsa-aortan aneurysmissä.

Key Words Abdominal aortic aneurysm - elastin - aorta - metalloenzymes

  http://www.bioscience.org/2005/v10/af/1503/figures.htm

Elastaasi ja aortan aneurysma. hypereglykemia kohotaa PAI-1 ilmenemää.

Hakusana:
ELASTASE and Aortic Aneyrysm- association
Search Pub Med 222 answers.
Results: 1 to 20 of 222

• (1) Hyperglykemian merkitys aortan aneurysmassa.

Miyama N, Dua MM et al. Hyperglycemia limits experimental aortic aneurysm progression.
J Vasc Surg. 2010 Jul 31.PMID: 20678880

CONCLUSIONS: Hyperglycemia reduces progression of experimental AAA disease; lowering of serum glucose levels with insulin treatment diminishes this protective effect. Identifying mechanisms of hyperglycemic aneurysm inhibition may accelerate development of novel clinical therapies for AAA disease

• (2) Ateroskleroosin ja vatsa-aortan aneurysmataudin riskiin  assosioituu kohonnut MMP-8 ja alentunut myeloperoksidaasi.

Pradhan-Palikhe P, Vikatmaa P et al.  Elevated MMP-8 and decreased myeloperoxidase concentrations associate significantly with the risk for peripheral atherosclerosis disease and abdominal aortic aneurysm. Scand J Immunol. 2010 Aug;72(2):150-7.PMID: 20618774
. Combination of high MMP-8 and low MPO level in serum eventually reflecting selectively modified neutrophil degranulation may indicate increased risk for arterial disease.

• (3) Transglutaminaasi 2 aktivoitumisen protektiivinen vaikutus  vatsa-aortan kehittymisen suhteen koe-eläimessä. TG2 mahdollisesti on  extrasellulaarimatriksia suojaava.

Munezane T, Hasegawa T et al. Activation of transglutaminase type 2 for aortic wall protection in a rat abdominal aortic aneurysm formation. J Vasc Surg. 2010 Jul 6 ]PMID: 20615646
 ---Similar mRNA upregulation of TNF-alpha, interleukin-1beta, matrix metalloproteinases (MMP)-2, MMP-9, and tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 was observed in the AAAs, and TG2 and TNF-alpha were colocalized in the aortic walls at 1 week.---
 Ex vivo experiments showed that mRNA expressions of TNF-alpha, MMP-2, and MMP-9 in the cultured AAA tissue were decreased by exogenous TG2, whereas were increased by cystamine (TG2 inhibitor) . TNF-alpha exposure to the AAA tissues was significantly upregulated TG2 mRNA expression (P = .0333).
CONCLUSION: TG2 expression and activity in AAA formation were enhanced, possibly due to compensatory reaction. TG2 has a potential role of ECM protector in aortic walls during remodeling of the AAAs.

• (4)  Vatsa-aortan aneurysman nopeaa kasvua heijastava seikka. Hp 2-1 fenotyyppi.   Elastaasi ja CRP koholla. 

Wiernicki I, Safranow K et al.  Haptoglobin 2-1 phenotype predicts rapid growth of abdominal aortic aneurysms. J Vasc Surg. 2010 Jun 4.
Elastase and C-reactive protein (CRP) levels are elevated in patients with AAAs.
Haptoglobin (Hp) polymorphism is associated with the prevalence and clinical evolution of many inflammatory diseases and atherosclerosis. Circulating neutrophils and neutrophil-associated proteases are an important initial component of experimental abdominal aortic aneurysm (AAA) formation.
CONCLUSIONS: The Hp 2-1 phenotype showed a strong association with increased rates of the expansion of AAAs and may be a useful independent predictor of growth rate. Further large follow-up studies will be needed to investigate the pathomechanisms of association and the role of elastase and inflammation in the progression of AAA

• (5) Hyperglysemia moduloi PAI-1 ilmenemää ja aortan diametria kokeellisessa aneurysmassa koe-eläimellä. Fibrinolyyttisellä tiellä on osuutta  vatsa-aortan aneurysman patofysiologiassa

Dua MM, Miyama N et al. Hyperglycemia modulates plasminogen activator inhibitor-1 expression and aortic diameter in experimental aortic aneurysm disease. Surgery. 2010 Aug;148(2):429-35. Epub 2010 Jun 19.PMID: 20561659
CONCLUSION: Hyperglycemia increases PAI-1 expression and attenuates AAA diameter in experimental AAA disease. These results emphasize the role of the fibrinolytic pathway in AAA pathophysiology, and suggest a candidate mechanism for hyperglycemic inhibition of AAA disease. Copyright 2010 Mosby, Inc. All rights reserved.

• (6.) Vatsa-aortan aneurysman ohuen trombin kattamassa pinnassa  on matrixia hajoittava proteolyyttinen aktiivisuus suurempaa kuin paksussa trombissa. Aortan elastiinin  säilyminen on tärkeää , jotta aneurysman muodostus estyisi. Jos trombi vaikuttaa ohuelta, elastaasiaktiivisuus voi olla kiihtyneempää.

Wiernicki I, Stachowska E et al. .Enhanced matrix-degrading proteolytic activity within the thin thrombus-covered wall of human abdominal aortic aneurysms.
Atherosclerosis. 2010 May 6.PMID: 20537648 

OBJECTIVE: The maintenance of an arterial elastin's integrity is essential in the prevention of abdominal aortic aneurysm (AAA) development. So far, the effect of intraluminal thrombus (ILT) thickness on the elastolytic activity within the AAA wall has not been studied. In the present study the hypothesis that thin thrombus is associated with enhanced proteolytic activity within human AAA wall was investigated

• (7). Jos trombiinilla aktivoituvan fibrinolyysin estäjän  karboksypeptidaasin (CPB)  aktiivisuus puuttuu, vatsa-aortan aneurysman muodostus kiihtyy koe-eläimellä.Katso kuva: http://atvb.ahajournals.org/content/30/7/1363/F5.large.jpg

Schultz G, Tedesco MM et al. Enhanced abdominal aortic aneurysm formation in thrombin-activatable procarboxypeptidase B-deficient mice. Arterioscler Thromb Vasc Biol. 2010 Jul;30(7):1363-70. Epub 2010 Apr 29.PMID: 20431069 [PubMed - indexed for MEDLINE]Related citations

OBJECTIVE: To determine whether procarboxypeptidase B (pCPB)(-/-) mice are susceptible to accelerated abdominal aortic aneurysm (AAA) development secondary to unregulated OPN-mediated mural inflammation in the absence of CPB inhibition. METHODS AND RESULTS: Thrombin/thrombomodulin cleaves thrombin-activatable pCPB or thrombin-activatable fibrinolysis inhibitor, activating CPB, which inhibits the generation of plasmin and inactivates proinflammatory mediators (complement C5a and thrombin-cleaved osteopontin [OPN]). Apolipoprotein E(-/-)OPN(-/-) mice are protected from experimental AAA formation. Murine AAAs were created via intra-aortic porcine pancreatic elastase (PPE) infusion. Increased mortality secondary to AAA rupture was observed in pCPB(-/-) mice at the standard PPE dose. At reduced doses of PPE, pCPB(-/-) mice developed larger AAAs than wild-type controls (1.01+/-0.27 versus 0.68+/-0.05 mm; P=0.02 [mean+/-SD]). C5(-/-) and OPN(-/-) mice were not protected against AAA development. Treatment with tranexamic acid inhibited plasmin generation and abrogated enhanced AAA progression in pCPB(-/-) mice. CONCLUSIONS: This study establishes the role of CPB in experimental AAA disease, indicating that CPB has a broad anti-inflammatory role in vivo. Enhanced AAA formation in the PPE model is the result of increased plasmin generation, not unregulated C5a- or OPN-mediated mural inflammation.
 TÄTÄ ASIAA TÄYTYY KATSOA TARKEMMIN. Muistiin 16.4. 2014. Päivitys jatkuu.

8.

Acoustic radiation force impulse imaging on ex vivo abdominal aortic aneurysm model.

Tierney AP, Dumont DM, Callanan A, Trahey GE, McGloughlin TM.

Ultrasound Med Biol. 2010 May;36(5):821-32. Epub 2010 Apr 9.PMID: 20381946 [PubMed - indexed for MEDLINE]Related citations

9.

Efficacy of neutrophil elastase inhibitor on type A acute aortic dissection.

Niino T, Hata M, Sezai A, Yoshitake I, Unosawa S, Fujita K, Shimura K, Osaka S, Minami K.

Thorac Cardiovasc Surg. 2010 Apr;58(3):164-8. Epub 2010 Apr 7.PMID: 20376727 [PubMed - indexed for MEDLINE]Related citations
BACKGROUND: Surgery for type A acute aortic dissection (AAD) is associated with a high mortality and incidence of postoperative complications, including acute respiratory failure and coagulopathy. Aim of the study was to investigate the effects of sivelestat on pulmonary function and coagulopathy in patients undergoing surgery for AAD.
METHODS: The platelet count, antithrombin III (AT III) level, leukocyte count, C-reactive protein (CRP) level, prothrombin time (PT), activated partial thrombin time (APTT), and prothrombin time-international normalized ratio (PT-INR) were measured.
 RESULTS: The postoperative decrease of AT III and the platelet count on admission to the intensive care unit (ICU) and 3 hours later were significantly less in group I. The leukocyte count and the values of CRP, PT, APTT, and PT-INR did not differ significantly between the groups. The duration of mechanical ventilation after surgery tended to be shorter in group I.
 CONCLUSIONS: Sivelestat significantly reduced the postoperative decreases in AT III and platelet count in patients undergoing emergency surgery for AAD. Georg Thieme Verlag KG Stuttgart New York

10.
Thrombus versus wall biological activities in experimental aortic aneurysms.
Coutard M, Touat Z, Houard X, Leclercq A, Michel JB.
J Vasc Res. 2010;47(4):355-66. Epub 2009 Dec 16.PMID: 20016209 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

11.
A novel rat model of abdominal aortic aneurysm using a combination of intraluminal elastase infusion and extraluminal calcium chloride exposure.
Tanaka A, Hasegawa T, Chen Z, Okita Y, Okada K.
J Vasc Surg. 2009 Dec;50(6):1423-32.PMID: 19958989 [PubMed - indexed for MEDLINE]Related citations
CONCLUSION: The rat AAA model using a combination of intraluminal elastase infusion and extraluminal calcium chloride exposure is simple and easy to perform and is highly reliable and reproducible to create a saccular aneurysm similar to human AAAs. This model could be more useful to clarify AAA pathogenesis, mechanisms, and treatment interventions in experimental researches.

12.
Smooth muscle phenotypic modulation is an early event in aortic aneurysms.
Ailawadi G, Moehle CW, Pei H, Walton SP, Yang Z, Kron IL, Lau CL, Owens GK.
J Thorac Cardiovasc Surg. 2009 Dec;138(6):1392-9.PMID: 19931668 [PubMed - indexed for MEDLINE]Related citations

13.
Nitric oxide induces the progression of abdominal aortic aneurysms through the matrix metalloproteinase inducer EMMPRIN.
Lizarbe TR, Tarín C, Gómez M, Lavin B, Aracil E, Orte LM, Zaragoza C.
Am J Pathol. 2009 Oct;175(4):1421-30. Epub 2009 Sep 24.PMID: 19779140 [PubMed - indexed for MEDLINE]Related citations

14.
Decreased collagen and increased matrix metalloproteinase-13 in experimental abdominal aortic aneurysms in males compared with females.
Cho BS, Roelofs KJ, Ford JW, Henke PK, Upchurch GR Jr.
Surgery. 2010 Feb;147(2):258-67. Epub 2009 Sep 20.PMID: 19767051 [PubMed - indexed for MEDLINE]Related citations

15.
Expression of annexin II in experimental abdominal aortic aneurysms.
Hayashi T, Morishita E, Ohtake H, Oda Y, Asakura H, Nakao S.
Int J Hematol. 2009 Oct;90(3):336-42. Epub 2009 Sep 16.PMID: 19756921 [PubMed - indexed for MEDLINE]Related citations
Annexin II is a receptor of tissue-type plasminogen activator (t-PA). We have previously identified annexin II by immunolocalization in human atherosclerotic abdominal aortic aneurysms (AAAs). To investigate possible interactions between annexin II and AAA development, we examined annexin II mRNA and protein expression in a rat model of experimental AAA. AAAs were induced in rats by transient aortic infusion of elastase.

16.
Critical role of mast cell chymase in mouse abdominal aortic aneurysm formation.
Sun J, Zhang J, Lindholt JS, Sukhova GK, Liu J, He A, Abrink M, Pejler G, Stevens RL, Thompson RW, Ennis TL, Gurish MF, Libby P, Shi GP.
Circulation. 2009 Sep 15;120(11):973-82. Epub 2009 Aug 31.PMID: 19720934 [PubMed - indexed for MEDLINE]Free PMC ArticleFree textRelated citations
CONCLUSIONS: High chymase-positive mast cell content in human AAA lesions, greatly reduced AAA formation in Mcpt4(-/-) mice, and significant correlation of serum chymase levels with human AAA expansion rate suggests participation of mast cell chymase in the progression of human and mouse AAA.

17.
Immune cells and molecular mediators in the pathogenesis of the abdominal aortic aneurysm.
Rizas KD, Ippagunta N, Tilson MD 3rd.
Cardiol Rev. 2009 Sep-Oct;17(5):201-10. Review.PMID: 19690470 [PubMed - indexed for MEDLINE]Related citations
Abdominal aortic aneurysm is a multifactorial disease with genetic risk factors and an immunologic component. Immune cells, including macrophages, neutrophils, mast cells, B- and T- lymphocytes, along with vascular smooth muscle cells and adventitial fibroblasts, produce cytokines and enzymes, promoting an inflammatory reaction, extracellular matrix (ECM) degradation, and neovascularization. Among the different enzymes secreted by immune and stromal cells, matrix metalloproteinase (MMP)-2, MMP-9, MMP-12, cathepsins, and neutrophil elastase (NE)  cause medial degeneration. Chymase causes smooth muscle cell apoptosis, and MMP-3, MMP-8, and MMP-13 cause adventitial collagen degradation, promoting abdominal aortic aneurysm rupture. At the same time chemokines (interleukin 8, macrophage inflammatory protein 1 alpha, monocyte chemotactic protein-1) cause recruitment and proliferation of inflammatory cells, whereas cytokines (vascular endothelial growth factor and transforming growth factor-beta) promote neoangiogenesis.

18.
Fusiform aneurysm model in rabbit carotid artery.
Reinald N, Fournier B, Naveau A, Couty L, Lemitre M, Seguier S, Coulomb B, Gogly B, Lafont A, Durand E.
J Vasc Res. 2010;47(1):61-8. Epub 2009 Aug 7.PMID: 19672109 [PubMed - indexed for MEDLINE]Related citations

19.
Creation of murine experimental abdominal aortic aneurysms with elastase.
Azuma J, Asagami T, Dalman R, Tsao PS.
J Vis Exp. 2009 Jul 23;(29). pii: 1280. doi: 10.3791/1280.PMID: 19629030 [PubMed - indexed for MEDLINE]Related citations

20.
Gender-dependent differential phosphorylation in the ERK signaling pathway is associated with increased MMP2 activity in rat aortic smooth muscle cells.
Ehrlichman LK, Ford JW, Roelofs KJ, Tedeschi-Filho W, Futchko JS, Ramacciotti E, Eliason JL, Henke PK, Upchurch GR Jr.
J Surg Res. 2010 May 1;160(1):18-24. Epub 2009 May 8.PMID: 19592018 [PubMed - indexed for MEDLINE]Related citations

These data provide evidence implicating alterations in p-ERK signaling via the up-regulation of MMPs as a potential explanation for gender-related discrepancies in AAA formation