Endothelin-1 and endothelial nitric oxide polymorphisms in idiopathic pulmonary arterial hypertension (original) (raw)
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Internal and Emergency Medicine, 2011
This study analyses the frequency and the potential role of two polymorphisms, the ?134del/insA, located in the gene encoding for Endothelin-1 (EDN1), and the His323His in the gene encoding for Endothelin receptor type A (EDNRA) in a cohort of 98 consecutive patients with pulmonary arterial hypertension from two different Cardiology Units (Mid-South of Italy), and in 100 healthy Caucasian subjects randomly recruited from the same area. Cardiac anatomy and function were analysed by non invasive diagnostic imaging techniques (Echocardiography standard m-mode, 2D, colour-Doppler) and by invasive studies (cardiac catheterization). Molecular screening of the region of interest was performed by automated sequencing. At univariate analysis, patients with the His323His TT genotype show a lower cardiac index (2 ± 0.6 vs. 2.3 ± 0.6; p = 0.05) and a higher indexed pulmonary vascular resistance (18.8 ± 9.6 vs. 14.2 ± 6.9; p = 0.01) at cardiac catheterization. A logistic multivariate model shows idiopathic disease (p = 0.01; OR = 3.8; CI = 1.3-11) and indexed pulmonary vascular resistances (p = 0.01; OR = 1.1; CI = 1-1.2) as independent predictors of TT genotype. Our findings may suggest a potential link between specific genotypes in the EDNRA gene and susceptibility for PAH.
Circulation, 2002
Background-A defect of nitric oxide (NO) synthesis in the lung of high-altitude pulmonary edema (HAPE) has been suggested to contribute to its exaggerated pulmonary hypertension. Several polymorphisms have been identified in the gene encoding endothelial nitric oxide synthase (eNOS), which is a key enzyme responsible for NO synthesis, some of which were reported to be associated with vascular disorders. Methods and Results-We studied 41 HAPE-susceptible subjects (HAPE-s) and 51 healthy climbers (control group) in a Japanese population. We examined 2 polymorphisms of the eNOS gene, including the Glu298Asp variant and 27-base pair (bp) variable numbers of tandem repeats using polymerase chain reaction followed by restriction fragment length polymorphism. The Asp allelic frequency of the Glu298Asp variant was 25.6% in the HAPE-s and 9.8% in the controls, which was significantly different between the two groups (Pϭ0.0044). The eNOS4a allelic frequency of 27-bp variable numbers of tandem repeats was 23.2% in the HAPE-s, significantly higher than that of 6.9% in the controls (Pϭ0.0016).
Heart, 2005
Nitric oxide (NO) is an important mediator of physiologic processes in the airways. Evidence exists that genetic factors affect NO formation and contribute to the pathophysiology of asthma. The aims of this study were to determine the endothelial NO synthase (eNOS) haplotypes in Czech asthmatics and control subjects and examine their relation to asthma. We analyzed a total of six polymorphisms. Two SNPs in the promoter (C-786T and C-691T), two variants in the introns (27-bp repeat in intron 4 and G11T in intron 23), and two others in the exons (C774T in exon 6 and G894T in exon 7) were genotyped in 610 subjects (asthma, n ϭ 294; healthy controls, n ϭ 316), and a case-control association study was conducted. No significant differences in allele or genotype frequencies for individual polymorphisms were observed between patients with asthma and controls after correction for multiple comparisons. Nevertheless, a G to T exchange in intron 23 was related with specific sensitization for feather (p ϭ 0.008, p corr Ͻ 0.05). However, the common haplotype -786T/-691C/27-bp 5 repeat variant/774C/ 894G/11T was associated with lower risk of asthma (p ϭ 0.001, p corr Ͻ 0.05, odds ratio ϭ 0.58, 95% confidence interval ϭ 0.46 -0.73). These findings suggest that endothelial NOS variants may be one of the factors participating in protection or susceptibility to asthma in our population.
American Journal of Hypertension, 2000
Endothelial nitric oxide synthase (eNOS), encoded by NOS3, is a potent regulator of vasomotor tone and peripheral resistance. Congenic experiments indicate that a chromosomal segment containing the rat eNOS gene contributes to rat spontaneous hypertension (HT). A role for NOS3 in onset of essential hypertension (HT) is, however, controversial. We therefore decided to test NOS3 polymorphisms in a set of patients who have an accentuated ability to show an existing genetic association. The 112 HT subjects had two HT parents and the normotensive (NT) subjects had two NT parents. All were Anglo-Celtic whites. The two most promising polymorphisms, viz, a biallelic variable number of tandem repeats (VNTR) in intron 4 and an exon 7 variant that leads to an amino acid change (Glu298Asp), were genotyped by PCR (and BanII digestion in the case of the latter). Frequency of the minor allele of the VNTR was 0.11 in the NT and 0.10 in the HT subjects (P ؍ ؍ .9). For the exon 7 variant, Asp298 frequency was 0.30 and 0.32 in each respective group (P ؍ ؍ .6). Tracking was seen for the Asp298 allele with elevation in body mass index (P ؍ ؍ .034), and the minor allele of the VNTR with elevation in LDL (P ؍ ؍ .007) and reduction in HDL (P ؍ ؍ .048). In conclusion, we saw no association of NOS3 markers with HT in the population studied. However, possible genotypic effects on plasma lipids and body mass index might warrant further studies, especially in view of possible associations with heart disease. Am J Hypertens 2000; 13:994 -998
Genetic Markers in Idiopathic Pulmonary Arterial Hypertension (IPAH)
INTERNATIONAL JOURNAL OF HUMAN GENETICS, 2009
Idiopathic pulmonary arterial hypertension (IPAH) is a rare disorder with abnormally raised pulmonary arterial pressure. In IPAH, the trigger of the endothelial injury may result from oxidative stress, hypoxia, shear stress, inflammation in conjunction with genetic susceptibility. These epigenetic factors may have an influence on cell growth, differentiation and normal homeostatic functions of the endothelium, by altering endothelial permeability, production of growth factors and coagulation factors. Lung inflammation can lead to increased levels of oxidants that may also contribute to the development of IPAH. When the production of ROS exceeds, the capacity of the cell to detoxify them decreases and the resulting oxidative stress may be harmful to the integrity of biological tissue. Since in IPAH there is disruption of pulmonary artery vasculature, the generation of free radicals may further aggravate tissue injury and in view of its role in defensive mechanism, qualitative variation of SOD, CAT, AAT in IPAH is investigated in the present study to correlate specific electromorphic associations in its etiopathogenesis. In conclusion the present study revealed that Oxidative stress pathway (ROS/RNS) and inflammatory components may act as modifiers in pathogenicity of IPAH.
Cardiology, 2010
and thus exerts antiatherogenic properties . According to available studies, impaired NO synthesis and subsequent worsening of endothelial functioning and vasoconstriction have been observed in patients with atherosclerosis or its risk factors and are thought to be independent predictors of cardiovascular events . However, in pathological conditions (inflammation, aging, hypertension, hypercholesterolemia, diabetes mellitus, shortage of cofactors, or hypoxia), NO readily reacts with abundant reactive oxygen species, resulting in the formation of reactive dinitrogen trioxide and peroxynitrite (ONOO -), which in turn leads to a considerable diminishing of the amount of NO involved in its typical reactions, such as vasodilation or platelet adhesion inhibition . The amount of NO may also be decreased due to the presence of polymorphisms within NOS leading to the formation of protein having little or no activity (dysfunctional protein) . Numerous studies have suggested that the presence of some polymorphisms within the eNOS gene may be associated with an increased risk of cardiovascular disease [9] , ischemic heart disease [10] , coronary spasm [11] , hypertension [12] and in-stent restenosis .
European review for medical and pharmacological sciences, 2014
INTRODUCTION Endothelial dysfunction is recognized as an early and initiating event in the pathogenesis of coronary artery disease. Gene polymorphisms of endothelial constitutive nitric oxide synthase (ecNOS), angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) have been found to be associated with atherosclerosis. We aimed to investigate the possible effects of ecNOS, ACE and AT1R gene polymorphisms on endothelial functions in healthy population. MATERIALS AND METHODS In 255 healthy subjects (male/female: 119/136 mean age 35.1±2.3 years) ecNOS, ACE and AT1R gene polymorphisms were assessed by polymerase chain reaction (PCR). Endothelium dependent (EDD, flow-mediated) and endothelium independent vasodilation (EID) were measured by high resolution brachial artery ultrasound and 0.5 mg sublingual nitroglycerine respectively. RESULTS ecNOS and ACE genes had no significant effect on EDD and EID. However, subjects with AT1RAC+CC genotypes had lower EDD compare...
Archivos de Bronconeumología (English Edition), 2014
Introduction: One of the pathways involved in pulmonary arterial hypertension (PAH) is the nitric oxide (NO) pathway. A polymorphism in the inducible NO synthase (NOS2) gene has been described, consisting of the CCTTT pentanucleotide repeat, which causes a reduction in NO production. The aim of this study was to determine if this polymorphism increases susceptibility to developing PAH. Methods: Sixty-four patients with a diagnosis of PAH groups i and iv and 50 healthy controls were compared. DNA genotyping of the samples for this polymorphism was performed using PCR. The distribution between both groups was compared and correlated with clinical and hemodynamic parameters and therapeutic response. Results: A significantly different distribution was observed in the number of repeats between patients and controls (P<.0001). When the samples were categorized by short forms (both alleles with less than 12 repeats) and long forms (≥12 repeats), it was observed that the former had an almost 4-fold risk of developing PAH (odds ratio: 3.83; 95% CI: 1.19-12.32, P=.024). There were no differences between the most common types of PAH, either in therapeutic response or survival. There was no correlation between hemodynamic parameters and the number of repeats in the patients, and only a weak correlation with systolic PAH. Conclusions: There are significant differences in the distribution of the NOS2 promotor CCTTT polymorphism between patients with PAH and the healthy population. A minor CCTTT pentanucleotide repeat in the NOS2 gene may increase the risk of developing PAH. A. Baloira Villar et al. / Arch Bronconeumol. 2014;50(4):141-145 superior de desarrollar HAP (odds ratio: 3,83; IC 95%: 1,32; p = 0,024). No hubo diferencias entre los tipos más frecuentes de HAP ni en la respuesta terapéutica o supervivencia. No existió correlación entre parámetros hemodinámicos y el número de repeticiones en los pacientes, solo débil correlación con la presión arterial pulmonar sistólica. Conclusiones: Existen diferencias significativas en la distribución del polimorfismo CCTTT del gen NOS2 entre pacientes con HAP y población sana. Una menor repetición del pentanucleótido CCTTT en el gen de la NOS2 podría incrementar el riesgo de desarrollar HAP.