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Amaç: Ateroskleroz sürecinde endotelyal hücrelerde enflamatuvar tepkimeleri aktive eden sinyal yolaklarını uyaran okside LDL, kardiyovasküler hastalıkların gelişiminde önemli bir patojenik faktör olarak tanımlanmaktadır. Endotel hücrelerinde okside LDL için başlıca reseptör olan okside LDL reseptörü (LOX1), okside LDL’leri endotel hücrelerinde özgül olarak bağlayabilme, hücre içine alabilme ve degrade edebilme özelliğine sahiptir. Bu çalışmada LOX-1’i kodlayan OLR1 geninde 3’UTR188C>T polimorfizminin koroner arter hastaları ve sağlıklı kontrollerden oluşan çalışma gruplarında serum okside LDL ve lipid düzeylerine etkisinin araştırılarak KAH hastalarında lipid parametrelerle ilişkisinin belirlenmesi amaçlanmıştır. Yöntem: Çalışmaya katılan 50 KAH hastası ve 34 sağlıklı kontrolden oluşan gruplarda OLR1 geni 3’UTR188C>T polimorfizminin tespiti için Polimeraz Zincir Reaksiyonu ve Restriksiyon Fragman Uzunluk Polimorfizmi yöntemleri kullanılmıştır. İstatistiksel analiz SPSS 20.0 ile yapılmıştır. Bulgular: KAH grubunda okside LDL (pT genotip ve allel dağılımları gruplar arasında benzer bulunmuştur (p>0,05). 188T alleli hem KAH (pT polimorfizminin hem proaterojenik bir molekül olan serum okside LDL hem de aterojenik lipid profili lehine etkileriyle KAH gelişimiyle ilişkili olabileceğine işaret etmektedir., Aim: Oxidized LDL, which stimulates signaling pathways that activate inflammatory reactions in endothelial cells during atherosclerosis, is defined as an important pathogenic factor in the development of cardiovascular diseases. The oxidized LDL receptor (LOX-1), which is the main receptor for oxidized LDL in endothelial cells, has the ability to specifically bind, internalize and degrade oxidized LDLs in endothelial cells. In this study, it was aimed to investigate the effect of 3'UTR188C>T polymorphism in the OLR1 gene encoding LOX-1 on serum oxidized LDL and lipid levels in the study groups consisting of coronary artery disease (CAD) patients and healthy controls, and to determine its relationship with lipid parameters in patients with CAD. Methods: Polymerase Chain Reaction and Restriction Fragment Length Polymorphism methods were used to detect the OLR1 gene 3'UTR188C>T polymorphism in groups of 50 CAD patients and 34 healthy controls. Statistical analyzes were performed with SPSS 20.0. Results: In the CAD group, oxidized LDL (pT genotype and allele distributions were found to be similar between the groups (p>0.05). The 188T allele was associated with higher oxidized LDL levels in both CAD (pT polymorphism may be associated with the development of CAD with its effects in favor of both serum oxidized LDL, which is a proatherogenic molecule, and an atherogenic lipid profile.

DOI : 10.26650/IstanbulJPharm.2019.18010 Caveolin-1 (CAV-1) plays a crucial role in endothelial-nitric oxide synthase (eNOS) enzymatic activity. Therefore, CAV-1 and eNOS interactions have a significant impact on endothelial dysfunction, cholesterol levels, and atherosclerosis. We investigated the critical variations in NOS3 and CAV1 genes in this case–control study to determine the relations between the coronary heart disease (CHD) risk factors. The NOS3-rs1799983, CAV-1 rs3840634, and rs3807990 variations were analyzed in 76 CHD patients and 91 controls using the polymerase chain reaction. Mean serum Total-cholesterol levels were significantly higher in CHD patients with the CAV-1 rs3807990-T allele than in patients with CC genotype (p=0.017). There was a statistically significant correlation between the rs3807990-T allele and hypercholesterolemia in the CHD group (p=0.008). The multivariate analysis confirmed that the CAV-1 rs3807990-T allele (p=0.011) is a risk factor for hypercholesterolemia. Moreover, the serum HDL-Cholesterol level was detected to be higher in patients carrying both CAV1-rs3807990-T and NOS3-rs1799983-T alleles than those with the CAV-1 rs3807990-CC/NOS3-rs1799983-GG genotype subgroup (p=0.013). These results suggested that the genetic variations of CAV-1 rs3807990 and NOS3-rs1799983 may contribute to the increased hypercholesterolemia risk and thus on the development of CHD. Cite this article as : Ilikay S, Coskunpinar E, Kurnaz-Gomleksiz O, Bugra Z, Eronat AP, Ozturk O, Yilmaz-Aydogan H (2019). Effects of common variations of NOS3 and CAV1 genes on hypercholesterolemic profile in coronary heart disease. Istanbul J Pharm 49 (2): 53-60.

Amaç: Vasküler endotelyumun antiaterojenik fonksiyonunun azalması endotel disfonksiyona sebep olmaktadır. Aterosklerotik sürecin gelişiminde önemli bir mekanizma olan endotel disfonksiyonu nitrik oksit (NO) düzeyinin azalmasıyla karakterizedir. NO miktarı, kendisini üreten eNOS enzim aktivitesinin kaveolin-1 (Cav-1) tarafından inhibisyonuyla düzenlenmektedir. Çalışmamızda diyabetik ve diyabetik-olmayan koroner kalp hastalığında (KKH) CAV1 rs3807990 varyasyonunun metabolik ve lipid biyobelirteçlerin düzeylerine etkisinin ve bu şekilde diyabetik dislipidemiye olası katkısının belirlenmesi amaçlanmıştır. Gereç ve Yöntem: CAV1 geni rs3807990 varyasyonu, 32 diyabetik ve 41 diyabetik-olmayan KKH hastasında Polimeraz Zincir Reaksiyonu-Restriksiyon fragman uzunluğu polimorfizmiyle değerlendirilmiştir. Bulgular: Diyabetik-olmayan KKH grubunda T alleli yüksek total-kolesterol düzeyleriyle ilişkilidir (p=0,021). T alleli taşıyan Diyabetik-KKH hastaları CC-genotiplilere göre yüksek LDL-K (p=0,037) ve glukoz düzeylerine sahip bulundu (p=0,076). Ayrıca diyabetik-KKH hastalarında T alleli serum trigliserid düzeylerinde artışla ilişkili bulunmuştur. Sonuç: Diyabetik-KKH’larda CAV1 rs3807990-T allelinin yüksek glukoz seviyeleriyle ilişkisinin trigliserid seviyelerinde de görülmesi glukoz-trigliserid metabolizması arasındaki ilişkiyle örtüşmektedir. Ayrıca T alleli her iki grupta hiperkolesterolemi ile ilişkili bulunmuştur. Bulgularımız CAV1 rs3807990-T allelinin KKH risk faktörlerinden hiperkolesterolemi gelişiminde etken genetik risk faktörleri arasında yer alabileceği, glukoz düzeylerindeki artışı etkileyebileceği ve bununla ilişkili olarak trigliserid yüksekliğine katkıda bulunabileceği ve sonuç olarak özellikle diyabetik hastalarda dislipidemik fenotipe katkısı olabileceğini önermektedir., Objective: A decreased antiatherogenic function of endothelium causes endothelial dysfunction characterized by decreased nitric oxide (NO) levels. NO amounts can be regulated by the inhibition of eNOS enzyme activity via caveolin-1 (Cav-1). We aimed to determine the effect of CAV1 rs3807990 on metabolic and lipid biomarker levels in diabetic and non-diabetic coronary heart disease (CHD) and to determine the possible contribution to diabetic dyslipidemia. Material and Methods: CAV1 rs3807990 was assessed by the Polymerase Chain Reaction-Restriction Fragment length Polymorphism in 32 diabetics and 41 non-diabetic CHD patients. Results: T allele is associated with high total-cholesterol levels in non-diabetic CHD patients (p=0.021). T-allele carriers in diabetic CHD patients had high LDL-C (p=0.037) and glucose levels (p=0.076) compared to the CC-genotype. In addition, the T allele in diabetic-CHD patients was associated with an increase in serum triglyceride levels. Conclusion: In diabetic-CHDs, the association of CAV1 rs3807990-T allele with high glucose and triglycerides was consistent with the relationship between glucose and triglyceride metabolism. T-allele was also found associated with hypercholesterolemia in both groups. CAV1 rs3807990-T allele may be one of the genetic risk factors for hypercholesterolemia and may cause an increase in glucose. It may also contribute to triglyceride elevation and, consequently, contribute to dyslipidemic phenotype, especially in diabetic-CHD patients.

In diabetes mellitus (DM) patients, left ventricular dysfunction is widely evaluated and established by conventional diagnostic methods, whereas right ventricular (RV) function is not as sufficiently evaluated. The aim of this study is to assess the preclinical effects of DM on RV function by using novel Tissue Doppler Imaging (TDI)-derived indices.The study included 96 patients with type II DM [60 with DM only and 36 patients with coexisting DM and hypertension (DMHT)] and 40 healthy controls. Conventional parameters and TDI-derived systolic velocities of tricuspid annulus [isovolumic myocardial acceleration (IVA), peak myocardial velocity during isovolumic contraction (IVV), peak systolic velocity during ejection period (Sa), RV Tei index] were measured.TDI-derived RV IVA was significantly lower in both DM and DMHT patients compared to controls indicating subclinical impairment in RV systolic function in the study patients (P = 0,0001). However RV IVA was similar in DM and DMHT subgroup supporting RV systolic impairment in DM was independent from HT. In correlation analysis, RV IVA was significantly correlated with the existence of diabetic nephropathy (r =-0,38; P = 0,003), retinopathy (r =-0,35; P = 0,006), insulin resistance (r =-0,52; P = 0,0001).Diabetes is associated with subclinical RV systolic dysfunction, regardless of coexisting hypertension. Tissue Doppler-derived IVA; is a novel, non-invasive parameter which may be used in early detection of RV systolic dysfunction in patients with DM.

Although right ventricular (RV) systolic dysfunction is an important indicator for the severity of mitral stenosis (MS), its diagnosis is difficult before systemic signs of venous congestion occur. We assessed the association between tissue Doppler (TDI)-derived isovolumic myocardial acceleration (IVA) and the severity of MS.The study included 112 MS patients (79 mild to moderate, 33 severe MS). Two-dimensional and Doppler echocardiographic parameters (mitral valve area, transmitral diastolic gradients, pulmonary artery pressure, RV fractional shortening, pulmonary flow acceleration time, tricuspid valve annular systolic excursion) were calculated. Additionally, TDI-derived systolic velocities of the tricuspid annulus (IVA, peak myocardial velocity during isovolumic contraction-IVV, peak systolic velocity during ejection period-Sa) were recorded. The results were compared with those of 60 age- and sex-matched healthy controls.All TDI-derived systolic velocities (IVV, Sa and IVA) were significantly decreased in patients with MS (p0.0001). However, IVA was the only parameter to distinguish the severity of MS (p0.0001). It also showed significant correlations with the following parameters with which IVV and Sa were not correlated: mitral valve area (r=0.79, p0.0001), mean (r=-0.54, p0.0001) and maximum (r=-0.58, p0.0001) transmitral diastolic gradients, pulmonary artery pressure (r=-0.54, p0.0001), and left atrial diameter (r=-0.68, p0.0001). The ROC curve analysis showed that an IVA of2.9 m/sec2 predicted MS patients with 86% sensitivity, 87% specificity, and an IVA of2 m/sec2 predicted severe MS with 82% sensitivity and 77% specificity.Tissue Doppler-derived right ventricular IVA may be used as an adjunctive, alternative noninvasive parameter to determine the severity of MS in patients without signs of systemic venous congestion.

Endothelial dysfunction may enhance platelet aggregation despite regular aspirin therapy. We investigated the relationship between aspirin-resistant platelet aggregation and endothelial dysfunction in patients with stable coronary artery disease.The study included 98 patients (60 males, 38 females; mean age 62+/-8 years) receiving medical treatment for stable coronary artery disease. Platelet function assays were performed with the Platelet Function Analyzer (PFA)-100 with collagen and epinephrine (Col/Epi) and collagen and adenosine diphosphate cartridges. Aspirin resistance was defined as a closure time of less than 186 seconds with Col/Epi cartridges despite regular aspirin therapy. Endothelial function was assessed via measurement of flow-mediated dilatation by brachial artery ultrasonography.Twenty patients (20.4%) were found to be aspirin-resistant by the PFA-100. There were no significant differences between patients with and without aspirin resistance with respect to the mean aspirin dose administered and other medications. The mean basal diameter of the brachial artery was 4.11 mm and the mean flow-mediated dilatation (percentage change from basal diameter) was 4.7% in patients with aspirin resistance. The corresponding figures were 4.14 mm and 5.3% in the absence of aspirin resistance (p0.05).In our study, endothelial dysfunction was found in all the patients with stable coronary artery disease, without any association of its presence and severity with aspirin resistance.

Hypertension and left ventricular hypertrophy (LVH) are important causes of morbidity and mortality in the population. Angiotensinogen (AGT) M235T polymorphism has been associated with LVH, left ventricular dimensions, coronary artery disease and antihypertensive drug response in previous studies. We examined relationship between AGT M235T polymorphism and echocardiographic left ventricular indices in a Turkish population of treated hypertensive patients with normal coronary arteries.In this cross-sectional study a Turkish population of 92 hypertensive patients treated in our outpatient clinic were enrolled. All patients had normal coronary angiographic examinations. Genotypes for AGT M235T were determined from peripheral leukocytes. Left ventricular dimensions, mass and function indices, after adjustment for clinical covariates were analyzed by multiple regression analysis according to genotypes.Genotype frequencies for AGT M235T were MM-24.7%, MT-52.8% and TT-22.5%. Left ventricular end-systolic (LVES) dimensions for AGT M235T MM, MT, TT genotypes were 17.9+/-4.2 mm, 19.4+/-6.2 mm, and 16.4+/-2.9 mm, respectively (p=0.08). Angiotensinogen M235T TT genotype showed a trend towards a lower LVES dimension but results were not statistically significant. Left ventricular ejection fractions for AGT M235T MM, MT, TT subgroups were 61.3+/-15.0%, 59.4+/-14.0%, and 67.8+/-8.5%, respectively (p=0.07). Angiotensinogen M235T TT genotype showed a tendency towards lower left ventricular mass index but results were not statistically significant. None of the AGT M235T genotypes predicted left ventricular dilatation, mass or function in treated hypertensive patients with normal coronary arteries.Angiotensinogen M235T polymorphism was not useful to predict left ventricular mass, function, hypertrophy or dilatation in a small population of treated Turkish hypertensive patients with normal coronary arteries.