MJESTO I ULOGA ENDOTELA U HIPERTENZIJI I ATEROSKLEROTSKIM PROCESIMA

DARKO POČANIĆ

Endotel je sve do prije dvadesetak godina bio smatran jednostavnom, pasivnom membranom koja prekriva unutar­nji sloj krvnih žila. Najvažnija funkcija, činilo se tada, bila je omogućiti nesmetano laminarno strujanje krvi. Mnoga istraživanja provedena u posljednjih tridesetak godina jasno su pokazala upravo suprotno. Endotel je vrlo aktivan organ, koji teži više od 1 kg i prekriva površinu od oko 700 četvornih metara kod prosječne osobe teške 70 kg. No, nije impresivna samo njegova veličina i građa od preko trilijun stanica, još je impresivnija složena uloga endotelnih stanica u normalnim proce­sima održavanja homeostaze i patofiziološkim mehanizmima oštećenja organa u aterosklerozi. Normalne endotelne stanice proizvode jedan od najpotentnijih vazodilatatora u organizmu: NO (dušični oksid). Dušični oksid je osnovni čimbenik vazoprotekcije te je njegova sinteza nužna za održavanje građe i funkcije endotela. Bradikinin isto tako inducira vazodilataciju direktno i putem NO, ali u manjoj mjeri od samog NO. Oštećenje funkcije endotela nastupa najčešće kao posljedica viška angiotenzina II, i to ponajprije lokalno stvorenog, te uz prisutnost LDL-kolesterola. Oksidacijom LDL-kolesterola i njego­vim prodorom u stijenku krvne žile počinje morfološko i funkcionalno oštećenje endotela. Ekspresija athezijskih molekula na unutarnjoj strani krvne žile privlači monocite koji potom nesmetano prodiru u stijenku, transformiraju se u makrofage i fagocitiraju oksidirani LDL. Sljedeći korak je formacija pjenaste stanice i u konačnici aterosklerotskog plaka. Povišena količina tkivnog angiotenzin-konvertirajućeg enzima ključna je u samom začetku endotelne disfunkcije, jer angiotenzin II oponira svim vazoprotektivnim učincima NO. Učinkovita blokada enzima pretvorbe angiotenzina ključna je u ranoj terapiji ne samo hipertenzije već i u prevenciji endotelne disfunkcije.

Summary. Endothelium was »discovered« as a separate organ in the last decades of the previous century. For a long time endothelial cells were considered as a very passive monolayer of cells just covering the inner part of vascular walls. The role of these cells was thought to be only a mechanical barrier between circulating blood and vascular structures. Nowadays, after a series of biochemical and experimental studies, one can name endothelium as an organ, covering approximately 700 sqaure meters, weighing about 1.5 kilos in an average male with weight of 70 kg. Not only its quantity, but also its function is amazing. The most prominent and first well studied function of endothelial cells is vasodilatation and vasoconstriction. Normal cells, which are intact and in function produce regularly one of the most important protecting agent in circulation: NO. Normal endothelial cells produce NO as a result of higher blood pressure or growing demand for oxygen. It is produced from aminoacid L-arginine as a result of enzyme activity: endothelial NO synthetase (eNOS). Interleukins also can increase production of NO. NO has also antiinflammatory efects, helping in reparation and healing processes. Prostacyclins are the second most important vasodilating agent produced in endothelium. On the other hand, vasoconstriction is also mediated via endothelium. Endothelin 1, angiotensin II and thromboxan A are produced in vascular wall by endothelial cells, acting as op- ponent to NO. ACE system is very active inside those cells, with permanent local angiotensin II formation, that mostly act on vascular wall itself. Effects of such generated angiotensin II stimulate activation of VCAM molecules, starting adhesion of monocytes, their penetration in vascular wall and activation. Acivated macrophages get in contact with oxidized LDL particles already inside the vascular wall, producing foam cells. That is the very begining of atherosclerosis. All negative effects of excess of angiotensin II should be reduced by effective therapy with ACE inhibitors or AT antagonists. Today it seems more important to act on excess in endothelial AII in order to regulate not only blood pressure, but long-term devastat- ing effects on target organs, preventing atherosclerosis.