Genetic-epidemiological analysis and analysis of gene expression of the renin-angiotensin system (RAS) in carotid atherosclerosis in humans

Beograd : [A. P. Kolaković]

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Molekularna biologija - Molekularna genetika ateroskleroze / Molecular biology - Molecular genetics of atherosclerosis

Karotidna ateroskleroza (KA) je hronična bolest koja započinje aktivacijom i nakupljanjem inflamatornih ćelija koje se pune lipidima u zidu arterijskog krvnog suda. Aterosklerotski plak sadrži lipidno jezgro, fibroznu kapu, akumulira glatke mišićne ćelije (GMĆ) i proteine ekstraćelijskog matriksa (EĆM). Renin-angiotensin system (RAS) ima ključnu ulogu u aktivaciji inflamacije u zidu krvnog suda. Glavni molekuli RAS su: angiotenzin-konvertujući enzim (ACE), angiotenzin-konvertujući enzim-homolog (ACE2), angiotenzin II receptori tipa 1 (ATR1) i tipa 2 (ATR2), ACE2 homolog (TMEM 27) i regulatorna RNK (miR-155). Angiotenzin II (Ang II) je glavni efektorni molekul RAS koji se sintetiše aktivnošću ACE, a razgrađuje aktivnošću ACE2. Ang II ostvaruje svoje efekte vezujuću se za ATR1 i ATR2. Efekti Ang II imaju važnu ulogu u regulaciji vaskularne homeostaze i to su: vazokonstrikcija, migracija, proliferacija i hipertrofija GMĆ, povećana sinteza EĆM i povećana produkcija matriks-metaloproteinaza (MMPs). Ekspresija ATR1 regulisana je sa miR-155. Balans između aktivacije i represije RAS može biti odlučujući u patološkom remodelovanju zida krvnog suda i patogenezi KA. Zato je važno ispitati funkcionalnu aktivaciju RAS sistema na lokalnom (tkivnom) nivou u karotidama i to na nivou ekspresije gena koji kodiraju za komponente RAS, enzime i receptore. Ekspresija gena je regulisana preko prisustva/odsustva različitih alelnih varijanti funkcionalnih polimorfizama u genima za RAS. Genetičko-epidemiološka studija gena RAS je urađena po pacijenti - kontrole dizajnu, na tri gena i tri polimorfizma. Ova studija obuhvatila je 750 ispitanika oba pola iz populacije Srbije, 505 pacijenata i 246 kontrola iste etničke pripadnosti. Urađena je studija asocijacije polimorfizma I/D u genu za ACE, polimorfizma A1166C u genu za ATR1 i polimorfizma A/G -1332 u genu za ATR2 sa nastankom KA, kliničkim parametrima KA, fenotipom plaka (stabilni (SAP) i nestabilni (NAP)), kliničkim događajima (prolazni ishemijski događaj (TIA) i cerebrovaskularni insult (CVI)) u Srbiji. Isti polimorfizmi su asocirani i sa ekspresijom gena u tkivu plaku KA. Analiza ekspresije gena RAS na nivou iRNK je urađena po istom dizajnu, na šest gena...

The carotid atherosclerosis (CA) is chronic disease, which begins with activation inflammatory cells and accumulation lipid in these cells within blood vessel wall. Atherosclerotic plaque containing a lipid core, fibrous cap, accumulates smooth muscle cells (GMC) and proteins of the extracellular matrix (ECM). The renin-angiotensin system (RAS) has a key role in activation of inflammation within blood vessel wall. The main components of the system are: angiotensin I-converting enzyme (ACE), angiotensin converting enzyme homolog (ACE2), angiotensin II receptor type 1 (ATR1), angiotensin II receptor type 2 (ATR2), ACE2 homolog (TMEM27) and regulatory RNA (miR-155). Angiotensin II (Ang II) is the main effector molecule of the RAS, which is synthesized by the activity of ACE and is cleaved by ACE2. Ang II achieves its effects by binding to ATR1 and ATR2. These effects has an important role in the regulation of vascular homeostasis and include the following: vasoconstriction, vascular smooth muscle cells (SMC) migration, proliferation and hypertrophy, increased synthesis of extracellular matrix (ECM) and enhanced production of matrix metalloproteinases (MMPs). The expression of ATR1 is regulated by the miR-155. The balance between activation and repression of RAS can be decisive in pathological remodeling of the vessel wall and the pathogenesis CA. It is therefore important to examine the functional activation of RAS at the local (tissue) level in carotid vessel wall at level of expression genes encoding for components of the RAS, enzymes and receptors. The gene expression of components of RAS is regulated through the presence/absence of different allelic variants of functional polymorphisms in these genes. The genetic epidemiological study for RAS genes was performed by case-control design and consisted of three genes and three polymorphisms within these genes. This study included 750 subjects of both sexes from the Serbian population, 505 patients and 246 controls of the same ethnic background. It is done genetic association study the ACE I/D, ATR1 A1166C and ATR2 A/G -1332 polymorphisms with occurrence of CA, clinical parameters of CA, (phenotypes of plaques (stable (SP) and unstable (USP)), clinical events of disease (transient ischemic attack (TIA) and cerebrovascular insult (CVI)) in Serbia...

karotidna ateroskleroza (KA), renin-angiotenzin sistem (RAS), ACE, ACE2, ATR1, ATR2, TMEM27, miR-155, polimorfizam u genu, ekspresija gena

carotid atherosclerosis (CA), renin-angiotensin system (RAS), ACE, ACE2, ATR1, ATR2, TMEM27, miR-155, gene polymorphism, mRNA exspression

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