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Vpliv zaviralcev proprotein konvertaze subtilizin/keksin tipa 9 na izražanje genov za koregulatorje tega encima pri bolnikih s koronarno boleznijo srca
ID Vehar, Mateja (Author), ID Zupan, Janja (Mentor) More about this mentor... This link opens in a new window, ID Šebeštjen, Miran (Comentor)

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Abstract
Koronarna bolezen srca (KBS), ki spada v skupino srčno-žilnih bolezni (SŽB), predstavlja glavni vzrok obolevnosti in umrljivosti v razvitih državah. Gre za stanje, pri katerem je miokard neustrezno oskrbovan s krvjo in kisikom, najpogosteje zaradi tvorbe oblog (plakov) v svetlini koronarnih arterij, kar ovira pretok krvi in vodi do ishemije srčne mišice. Pomemben dejavnik tveganja za nastanek KBS predstavljajo predvsem visoke vrednosti holesterola lipoproteina nizke gostote (LDL-hol). Posledično predstavljajo terapije, ki znižujejo njegovo koncentracijo, zlati standard na področju zdravljenja SŽB. V zadnjih letih je proprotein konvertaza subtilizin/keksin tipa 9 (PCSK9) postala pomembna terapevtska tarča v okviru terapij za zniževanje LDL-hol. Ta namreč spodbuja razgradnjo receptorja za lipoprotein nizke gostote (LDLR), kar se odraža v zvišanih ravneh LDL-hol v krvi. Zaviralci PCSK9 z zavrtjem razgradnje LDLR vplivajo na znižanje LDL-hol v krvi ter na ta način predstavljajo optimističen pristop za zmanjševanje hiperlipidemij. V okviru magistrskega dela smo želeli ugotoviti razlike v izražanju genov, potencialnih koregulatorjev PCSK9, pri bolnikih s KBS pred in po šestih mesecih zdravljenja z zaviralci PCSK9 ter pri zdravih preiskovancih. Meritve smo izvedli na vzorcih komplementarne DNA (cDNA), ki so bili predhodno pridobljeni iz ribonukleinske kisline, izolirane iz periferne krvi preiskovancev. Optimizirali smo metodo kvantitativne verižne reakcije s polimerazo (qPCR) za merjenje izražanja štirih genov: SREBP1, SREBP2, LDLR in LIPC. Ti geni kodirajo proteine, ki delujejo kot koregulatorji PCSK9. Na podlagi rezultatov smo ugotovili, da se izražanje genov SREBP2, LDLR in LIPC razlikuje med bolniki s KBS in zdravimi preiskovanci, in sicer je bilo izražanje gena SREBP2 statistično značilno nižje, izražanje genov LDLR in LIPC pa statistično značilno višje pri bolnikih s KBS v primerjavi z zdravimi preiskovanci. Ugotovili smo tudi, da zdravljenje z zaviralci PCSK9 vpliva na izražanje genov SREBP2 in LIPC. Po šestih mesecih zdravljenja se je namreč izražanje gena SREBP2 statistično značilno povišalo, gena LIPC pa statistično značilno znižalo v primerjavi z začetnim izražanjem pred terapijo. Statistično značilnih razlik v izražanju genov, ki kodirajo koregulatorje PCSK9, nismo ugotovili med skupinama bolnikov, ki sta prejemali različni vrsti zaviralcev PCSK9. Področje vpletenosti proučevanih genov v regulacijo PCSK9 in razvoj KBS je slabo raziskano, zato s pridobljenimi rezultati študije težko naredimo splošne zaključke. Za vpogled v jasnejšo vzročno-posledično povezavo med vplivom zaviralcev PCSK9 na izražanje genov koregulatorjev tega encima ter spremembami v lipidnem profilu bi bilo v prihodnje smiselno ugotoviti, ali so spremembe v lipidnem profilu, kot posledica zdravljenja z zaviralci PCSK9, povezane s spremembami v izražanju preiskovanih genov.

Language:Slovenian
Keywords:koronarna bolezen srca, zaviralci proprotein konvertaze subtilizin/keksin tipa 9, koregulatorji PCSK9, izražanje genov, qPCR
Work type:Master's thesis/paper
Organization:FFA - Faculty of Pharmacy
Year:2024
PID:20.500.12556/RUL-160753-74ad8cd3-00c2-9b81-f783-414c10d244e5 This link opens in a new window
Publication date in RUL:04.09.2024
Views:191
Downloads:43
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Secondary language

Language:English
Title:The influence of proprotein convertase subtilisin/kexin type 9 inhibitors on this enzyme’s coregulators’ gene expression in coronary artery disease patients
Abstract:
Coronary heart disease (CHD), a type of cardiovascular disease (CVD), is the leading cause of morbidity and mortality in developed countries. CHD is characterised by the myocardium being undersupplied with blood and oxygen, most commonly due to plaques forming in the lumen of the coronary arteries. This obstructs blood flow and causes myocardial ischemia. One of the most significant risk factors for the development of CHD are high levels of low-density lipoprotein cholesterol (LDL-C). Consequently, therapies that lower its concentration are the gold standard in CVD treatment. In recent years, proprotein convertase subtilisin/kexin type 9 (PCSK9) has become a crucial therapeutic target in therapies aimed at reducing LDL-C as PCSK9 promotes the degradation of the low-density lipoprotein receptor (LDLR). Consequently, this is reflected in elevated LDL-C levels in the blood. By inhibiting the degradation of LDLR, PCSK9 inhibitors lower LDL-C levels in the blood. Thus, they are proving to be an optimistic way to reduce hyperlipidaemias. This master's thesis aims to determine the differences in gene expression, potential PCSK9 coregulators, in patients with CHD before and after a six-month treatment with PCSK9 inhibitors, compared to healthy subjects. Measurements were carried out on complementary DNA (cDNA) samples previously obtained from ribonucleic acid (RNA) isolated from the subjects’ the peripheral blood. The quantitative polymerase chain reaction (qPCR) method was optimized in order to measure the expression of four genes: SREBP1, SREBP2, LDLR, and LIPC. These genes encode proteins that act as coregulators of PCSK9. The results pointed to a difference in the expression of the SREBP2, LDLR, and LIPC genes in CHD patients compared to healthy subjects, with statistically significantly lower SREBP2 gene expression and statistically significantly higher LDLR and LIPC gene expression in CHD patients compared to healthy subjects. The findings also suggested that treatment with PCSK9 inhibitors affects the expression of the SREBP2 and LIPC genes. After six months of treatment, the expression of the SREBP2 gene was statistically markedly higher, while the expression of the LIPC gene was significantly lower compared to the pre-treatment baseline expression. No statistically significant variation in the expression of genes encoding PCSK9 coregulators was found between the two groups of patients receiving different types of PCSK9 inhibitors. Since the link between the genes examined in this study and how they affect the regulation of PCSK9 and therefore the development of CHD is currently still under-researched, it is difficult to draw general conclusions based on the results of the present study. To gain a clearer insight into how the PCSK9 inhibitors affect the expression of genes co-regulating the PCSK9 enzyme and the subsequent changes in the lipid profile, future research should be aimed at determining whether changes in the lipid profile resulting from treatment with PCSK9 inhibitors are associated with changes in the expression of the genes examined in this master’s thesis.

Keywords:coronary heart disease, proprotein convertase subtilisin/kexin type 9 inhibitors, PCSK9 coregulators, gene expression, qPCR

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