Koroner arter hastalarında mitokondriyal hasar belirteçleri ve ilgili genlerin ekspresyonu
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Tarih
2024
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Yayıncı
Selçuk Üniversitesi, Sağlık Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Kardiyovasküler hastalıklar, dünya çapında morbidite, mortalite ve sağlık harcamaları' nın önde gelen nedenidir. Hiperkolesterolemi, koroner arter hastalığı (KAH) gibi aterosklerotik hastalıkların gelişmesine yol açan önemli bir risk faktörüdür. Son zamanlarda yapılan çalışmalarda apoptotik veya nekrotik hücre ölümlerinde ve hücresel strese bağlı olarak mitokondriyal kalite kontrol mekanizmalarının başarısız olduğu durumlarda, mitokondriyal DNA'nın (ccf-mtDNA) hücreden dışarı çıkarak sistemik dolaşıma geçtiği ve hasarla ilişkili moleküler paternler (DAMP) olarak görev aldığı bildirilmektedir. Çalışmamızda, bu bilgilerden yola çıkarak endikasyonu gereği statin türevi ilaçları kullanan bireylerde statinlerin, mitokondriyal biyogenezi gösteren, AKT-1 ve PGC-1α ile mtDAMP olarak bilinen ve mitokondriyal hasarla ilişkilendirilmiş mtDNA, TFAM parametreleri ve de KLU'nun üzerine olan etkileri değerlendirildi. Çalışmamızda Selçuk Üniversitesi Tıp Fakültesi Hastanesi Kardiyoloji polikliniğine başvuran, endikasyonları kapsamında hiperkolesterolemi tedavisi alan 40 KAH ve rutin kontrol için gelen 40 sağlıklı bireyin serum Peroksizom Proliferatörleri ile Aktifleştirilen Reseptör Gama Koaktivatörü 1-Alfa (PGC1α), Mitokondriyal Transkripsiyon Faktörü A (TFAM), Klusterin (KLU), Rac-alfa Serin, Treonin-protein Kinaz (AKT-1) düzeyleri, aynı parametrelerin tam kan gen ekspresyon düzeyleri ile mtDNA serum düzeyleri ve kopya sayısı değerlendirildi. Elde edilen verilerin istatistiği SPSS 26 paket programı kullanılarak yapıldı. Ayrıca MEDCALC programı ile bu parametrelerin Receiver operating characteristic (ROC) eğrisi kullanılarak hastalığı ön görme gücü belirlendi. Analizler sonrası yapılan değerlendirmede p<0,05 düzeyleri istatistiksel olarak anlamlı kabul edildi. Elde edilen sonuçlara göre KAH grubunun sağlıklı kontrollere göre KLU ((3,41 (0,23-8,67)-1,12 (0,04-4,95)), TFAM (2,35 (0,11-5,80)-1,50 (0,03-4,34)) ve PGC-1α ((1,89 (0,00-10,70)-0,40 (0,02-0,99)) genlerinin ekspresyon düzeyleri anlamlı düzeyde yüksek bulundu (P=0,000; P=0,026; P=0,000). KAH grubunun kontrol grubuna göre serum KLU ((34,79 (10,60-211,49)-28,77 (6,64-64,81) ng/ml) ve TFAM ((246,095 (179,04-1672,15)-199,55 (31,68-640,05) ng/L) düzeylerinin daha yüksek olduğu tespit edildi (sırasıyla; P=0,001; P=0,029). Diğer parametreler arasında istatiksel olarak anlamlı bir fark bulunamadı. Kontrol grubunda, TFAM ve KLU protein düzeyleri, TFAM ve KLU gen ekspresyon düzeyleri, mtDNA kopya sayısı ile serum mtDNA düzeyleri arasında güçlü pozitif korelasyon tespit edildi. KAH grubunda, TFAM ve KLU protein düzeyleri, AKT-1 ve PGC-1α gen ekspresyon düzeyleri, mtDNA kopya sayısı ile serum mtDNA düzeyleri arasında güçlü pozitif korelasyon tespit edildi. Serum TFAM ve KLU düzeyleri KAH grubunda yüksek düzeylerde bulunmasına rağmen, ROC analiz sonuçlarına göre sadece serum TFAM'ın prognostik belirteç olarak kullanılabileceği tespit edilmiştir. Ayrıca TFAM, PGC-1α, KLU gen ekspresyon düzeylerinin ROC analiz sonuçlarına göre prognostik belirteç olarak kullanılabileceği bulunmuştur. Bu parametrelerden PGC-1α, KLU ve TFAM'ın yakın gelecekte tanı ve tedavi sürecinde daha önemli hale geleceğini ve rutin kullanılan biyobelirteçler arasına dahil olabileceğini düşünmekteyiz.
Cardiovascular diseases are the leading cause of morbidity, mortality and health expenditure worldwide. Hypercholesterolemia is a major risk factor for the development of atherosclerotic diseases such as coronary artery disease (CAD). Recent studies have reported that in apoptotic or necrotic cell death and in cases where mitochondrial quality control mechanisms fail due to cellular stress, mitochondrial DNA (ccf-mtDNA) exits the cell and enters the systemic circulation and acts as damage associated molecular patterns (DAMP). Based on this information, we evaluated the effects of statins on AKT-1 and PGC-1α, which indicate mitochondrial biogenesis, and mtDNA, TFAM parameters known as mtDAMP, which are associated with mitochondrial damage and mtDNA, TFAM parameters and CLU in individuals using statin-derived drugs as indicated. In our study, serum Peroxisome Proliferators Activated Receptor Gamma Coactivator Gamma Coactivator 1-Alpha (PGC1α) levels were measured in 40 CAD patients admitted to the Cardiology outpatient clinic of Selçuk University Faculty of Medicine Hospital and treated for hypercholesterolemia within the scope of the indications and in 40 healthy individuals who came for routine control, Mitochondrial Transcription Factor A (TFAM), Klusterin (KLU), Rac-alpha Serine, Threonine-protein Kinase (AKT-1) levels, whole blood gene expression levels of the same parameters and mtDNA serum levels and copy number were evaluated. The statistical analysis of the obtained data was performed using SPSS 26 package program. In addition, the predictive power of these parameters was determined by using Receiver operating characteristic (ROC) curve with MEDCALC program. After the analyses, p<0,05 levels were considered statistically significant. According to the results obtained, the expression levels of KLU ((3,41 (0,23-8,67)-1,12 (0,04-4,95)), TFAM (2,35 (0,11-5,80)-1,50 (0,03-4,34)) and PGC-1α ((1,89 (0,00-10,70)-0,40 (0,02-0,99)) genes were significantly higher in the CAD group compared to healthy controls (P=0,000, P=0,026, P=0,000). Serum KLU ((34,79 (10,60-211,49)-28,77 (6,64-64,81) ng/ml) and TFAM ((246,095 (179,04-1672,15)-199,55 (31,68-640,05) ng/L) levels were higher in the CAD group compared to the control group (P=0,001; P=0,029, respectively). No statistically significant difference was found between the other parameters. In the control group, there was a strong positive correlation between TFAM and KLU protein levels, TFAM and KLU gene expression levels, mtDNA copy number and serum mtDNA levels. In the CAD group, there was a strong positive correlation between TFAM and KLU protein levels, AKT-1 and PGC-1α gene expression levels, mtDNA copy number and serum mtDNA levels. Although serum TFAM and CLU levels were found to be high in the CAD group, it was determined that only serum TFAM could be used as a prognostic marker according to ROC analysis results. In addition, it was found that TFAM, PGC-1α, CLU gene expression levels could be used as a prognostic marker according to ROC analysis results. We think that PGC-1α, KLU and TFAM will become more important in the diagnosis and treatment process in the near future and may be included among the routinely used biomarkers.
Cardiovascular diseases are the leading cause of morbidity, mortality and health expenditure worldwide. Hypercholesterolemia is a major risk factor for the development of atherosclerotic diseases such as coronary artery disease (CAD). Recent studies have reported that in apoptotic or necrotic cell death and in cases where mitochondrial quality control mechanisms fail due to cellular stress, mitochondrial DNA (ccf-mtDNA) exits the cell and enters the systemic circulation and acts as damage associated molecular patterns (DAMP). Based on this information, we evaluated the effects of statins on AKT-1 and PGC-1α, which indicate mitochondrial biogenesis, and mtDNA, TFAM parameters known as mtDAMP, which are associated with mitochondrial damage and mtDNA, TFAM parameters and CLU in individuals using statin-derived drugs as indicated. In our study, serum Peroxisome Proliferators Activated Receptor Gamma Coactivator Gamma Coactivator 1-Alpha (PGC1α) levels were measured in 40 CAD patients admitted to the Cardiology outpatient clinic of Selçuk University Faculty of Medicine Hospital and treated for hypercholesterolemia within the scope of the indications and in 40 healthy individuals who came for routine control, Mitochondrial Transcription Factor A (TFAM), Klusterin (KLU), Rac-alpha Serine, Threonine-protein Kinase (AKT-1) levels, whole blood gene expression levels of the same parameters and mtDNA serum levels and copy number were evaluated. The statistical analysis of the obtained data was performed using SPSS 26 package program. In addition, the predictive power of these parameters was determined by using Receiver operating characteristic (ROC) curve with MEDCALC program. After the analyses, p<0,05 levels were considered statistically significant. According to the results obtained, the expression levels of KLU ((3,41 (0,23-8,67)-1,12 (0,04-4,95)), TFAM (2,35 (0,11-5,80)-1,50 (0,03-4,34)) and PGC-1α ((1,89 (0,00-10,70)-0,40 (0,02-0,99)) genes were significantly higher in the CAD group compared to healthy controls (P=0,000, P=0,026, P=0,000). Serum KLU ((34,79 (10,60-211,49)-28,77 (6,64-64,81) ng/ml) and TFAM ((246,095 (179,04-1672,15)-199,55 (31,68-640,05) ng/L) levels were higher in the CAD group compared to the control group (P=0,001; P=0,029, respectively). No statistically significant difference was found between the other parameters. In the control group, there was a strong positive correlation between TFAM and KLU protein levels, TFAM and KLU gene expression levels, mtDNA copy number and serum mtDNA levels. In the CAD group, there was a strong positive correlation between TFAM and KLU protein levels, AKT-1 and PGC-1α gene expression levels, mtDNA copy number and serum mtDNA levels. Although serum TFAM and CLU levels were found to be high in the CAD group, it was determined that only serum TFAM could be used as a prognostic marker according to ROC analysis results. In addition, it was found that TFAM, PGC-1α, CLU gene expression levels could be used as a prognostic marker according to ROC analysis results. We think that PGC-1α, KLU and TFAM will become more important in the diagnosis and treatment process in the near future and may be included among the routinely used biomarkers.
Açıklama
Anahtar Kelimeler
Biyobelirteçler, Biomarkers, DNA hasarı, DNA damage, DNA-mitokondrial, DNA-mitochondrial, Gen ifadesi, Gene expression, Hiperkolesterolemi, Hypercholesterolemia, Genler, Genes
Kaynak
WoS Q Değeri
Scopus Q Değeri
Cilt
Sayı
Künye
Erbayram, F. Z. (2024). Koroner arter hastalarında mitokondriyal hasar belirteçleri ve ilgili genlerin ekspresyonu. (Doktora Tezi). Selçuk Üniversitesi, Sağlık Bilimleri Enstitüsü, Konya.
