Áhrif thrombins og annarra áverkunarefna á æðaþel. Hlutverk AMP-kínasa og sveigðra boðleiða - verkefni lokið

Fréttatilkynning verkefnisstjóra

22.3.2018

Þrombín og virkjað protein C (APC) gegna lykilhlutverki í storkukerfi blóðs en virkja einnig boðkerfi í æðaþelsfrumum með því að kljúfa viðtaka á yfirborði æðaþelsins. Viðtakarnir nefnast PAR1 (protease activated receptor 1) sem eftir örvun virkja fjölda boðleiða sem síðan hrinda af stað fjölmörgum frumuviðbrögðum. Þótt thrombin og APC virki sama PAR1 viðtakann hafa þau gagnstæða verkun. Thrombin örvar storkumyndun, er bólguvaki og eykur gegndræpi æðaþels. APC hamlar storkumyndun, dregur úr bólgu og gegndræpi. Þetta fyrirbæri kallast PAR1 þversögnin sem hefur ekki verið að fullu skýrð.

Eins og við mátti búast jók thrombin bæði tjáningu viðloðunarsameinda í æðaþelsfrumum og fosfórun á léttum myosinkeðjum ásamt myndun átaksþráða (stress fibers) í frumunum, hvort tveggja merki þess að gegndræpi aukist við thrombinörvun æðaþels. Örvun AMPK hindraði tjáningu viðloðunarsameinda en hafði ekki áhrif á fosfórun léttra myosinkeðja. Gagnstætt því sem búist var við dró APC lítið sem ekkert úr thrombin áhrifunum á æðaþel. Þvert á móti þá virkaði APC í sömu átt og thrombin en með minni styrk.

Þessar niðurstöður benda til þess að verndunaráhrif APC gegn thrombin áhrifum á æðaþel séu ekki eins eindregin og fyrri rannsóknir hafa bent til. Hins vegar eru þær í fullu samræmi við nýlegar klíniskar slembirannsókir sem sýndu engin verndunaráhrif af APC í meðferð á blóðsýklunarlosti (sepstic shock).

Afurðir:

Sigurður Trausti Karvelsson: Master of Science Thesis: Effect of thrombin and other PAR1 agonists on endothelium. Role of AMP-kinase and biased signaling. University of Iceland, School of Health Sciences, Faculty of Medicine, June 2017.

_{Sigurður Trausti Karvelsson: Effect of thrombin and other PAR1 agonists on endothelial cells. Role of AMP-kinase and biased signaling. The 18th Conference on Research in Biomedical and Health Sciences. January 4th, 2017, Háskóli Íslands. Abstr.}

_English:

_{Thrombin and activated protein C (APC) are key hemostatic serine proteases that initiate cellular signalling by cleavage of protease activated receptors (PARs), thus liberating a new amino acid sequence known as a tethered ligand, which then activates the initial receptor and induces multiple signalling pathways and cell responses. The most important PAR receptor expressed on most cell types is PAR1 which is cleaved by both APC and thrombin. Despite acting upon the same receptor they trigger divergent effects. APC is an anticoagulant with antiinflammatory and cytoprotective effects, whereas thrombin is a protease with procoagulant and proinflammatory effects. This phenomenon has been called the PAR1 paradox and has not been fully explained.}

_{The main objective of the project was to delineate inflammatory versus antiinflammatory signaling in response to PAR-1 activation in cultured human endothelial cells and thus test the following hypothesis: The anti-inflammatory and cytoprotective effects following PAR-1 stimulation by activated protein C (APC) are mediated by the energy sensor AMP-activated kinase (AMPK).}

_{As expected, thrombin caused both increased expression of adhesion molecules and phosphorylation of myosin light chain leading to stress fiber formation and cell contraction, indicative of  increased permeability. AMPK activators prevented the increase in expression of adhesion molecules, but not myosin light chain phosphorylation. Surprisingly, APC did not prevent any of the effects of thrombin but rather had effects in the same direction as thrombin, albeit with much lower potency.}

_{Our results suggest that the protective effects of APC are not as robust as previously  suggested. They are, however, consistent with the lack of protective effect of APC recently experienced in randomized clinical trials of septic shock treatment.}

_Outputs:

_{Sigurður Trausti Karvelsson: Master of Science Thesis: Effect of thrombin and other PAR1 agonists on endothelium. Role of AMP-kinase and biased signaling. University of Iceland, School of Health Sciences, Faculty of Medicine, June 2017.}

_{Sigurður Trausti Karvelsson: Effect of thrombin and other PAR1 agonists on endothelial cells. Role of AMP-kinase and biased signaling. The 18th Conference on Research in Biomedical and Health Sciences. January 4th, 2017, Háskóli Íslands. Abstr.}

Heiti verkefnis: Áhrif thrombins og annarra áverkunarefna á æðaþel. Hlutverk AMP-kínasa og sveigðra boðleiða.
Verkefnisstjóri: Guðmundur Þorgeirsson, Háskóla Íslands
Tegund styrks: Verkefnisstyrkur
Styrktímabil: 2015-2016
Fjárhæð styrks: 12,4 millj. kr. alls
Tilvísunarnúmer Rannís:  152660