Ignatovica, V., G. Latkovskis, R. Peculis, K. Megnis, H.B. Schioth, I. Vaivade, D. Fridmanis, V. Pirags, A. Erglis, and J. Klovins, Single nucleotide polymorphisms of the purinergic 1 receptor are not associated with myocardial infarction in a Latvian population. Mol Biol Rep, 2011.
http://www.ncbi.nlm.nih.gov/pubmed/21643756
Kopsavilkums
The purinergic 1 receptor (P2RY1) has been implicated in development of heart disease and in individual pharmacodynamic response to anticoagulant therapies. However, the association of polymorphisms in the P2RY1 gene with myocardial infarction (MI), and its associated conditions, has yet to be reported in the literature. We evaluated seven known SNPs in P2RY1 for association with MI in a Latvian population. Seven independent parameters that are related to MI [body mass index (BMI), type 2 diabetes (T2D), angina pectoris, hypertension, hyperlipidemia, atrial fibrillation and heart failure] were investigated. No significant association with MI was observed for any of the polymorphisms. Those SNPs for which the P value was close to significance were located in coding or promoter regions. Intriguingly, carriers of the minor allele in the P2RY1 gene locus showed a tendency towards higher onset age for MI, suggesting a possible protective effect of these SNPs against MI or their contribution in progression as opposed to onset. Finally, a linkage disequilibrium (LD) plot was generated for these polymorphisms in the Latvian population. The results of this study suggest that the role of P2RY1 in individuals from Latvian population is likely to be principally involved in platelet aggregation and thromboembolic diseases, and not as a significant contributing factor to the global metabolic syndrome.
Ignatovica, V., K. Megnis, M. Lapins, H.B. Schioth, and J. Klovins, Identification and analysis of functionally important amino acids in human purinergic 12 receptor using a Saccharomyces cerevisiae expression system. FEBS J, 2011.
http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2011.08410.x/pdf
Kopsavilkums
The purinergic 12 receptor (P2Y12) is a major drug target for anticoagulant therapies, but little is known about the regions involved in ligand binding and activation of this receptor. We generated four randomized P2Y12 libraries and investigated their ligand binding characteristics. P2Y12 was expressed in a Saccharomyces cerevisiae model system. Four libraries were generated with randomized amino acids at positions 181, 256, 265 and 280. Mutant variants were screened for functional activity in yeast using the natural P2Y12 ligand ADP. Activation results were investigated using quantitative structure-activity relationship (QSAR) models and ligand-receptor docking. We screened four positions in P2Y12 for functional activity by substitution with amino acids with diverse physiochemical properties. This analysis revealed that positions E181, R256 and R265 alter the functional activity of P2Y12 in a specific manner. QSAR models for E181 and R256 mutant libraries strongly supported the experimental data. All substitutions of amino acid K280 were completely inactive, highlighting the crucial role of this residue in P2Y12 function. Ligand-receptor docking revealed that K280 is likely to be a key element in the ligand-binding pocket of P2Y12. The results of this study demonstrate that positions 181, 256, 265 and 280 of P2Y12 are important for the functional integrity of the receptor. Moreover, K280 appears to be a crucial feature of the P2Y12 ligand-binding pocket. These results are important for rational design of novel antiplatelet agents.
Peculis, R., G. Latkovskis, L. Tarasova, V. Pirags, A. Erglis, and J. Klovins, A Nonsynonymous Variant I248L of the Adenosine A3 Receptor Is Associated with Coronary Heart Disease in a Latvian Population. DNA Cell Biol, 2011.
http://www.ncbi.nlm.nih.gov/pubmed/21675873
Kopsavilkums
Adenosine plays an important part in the cardiac response to ischemia and reperfusion. The human adenosine receptor A3 (A3R), along with other adenosine receptors, is involved in mediation of those effects. The aim of the study was to ascertain whether the nonsynonymous single-nucleotide polymorphism (SNP) I248L (reference SNP ID: rs35511654) located in the A3R gene is associated with coronary heart disease (CHD). DNA samples from 683 individuals with CHD and from 826 control subjects selected from the Latvian Genome Database were successfully screened for rs35511654 using the TaqMan SNP Genotyping Assay. We observed a significantly decreased frequency of the rs35511654 C allele in a group of CHD patients compared with that in controls (p = 0.009). The association remained significant after adjustment for age, sex, and other nongenetic factors (p = 0.02). These results suggest that A allele of rs35511654 may predispose to CHD.
Ignatovica, V., R. Petrovska, D. Fridmanis, and J. Klovins, Expression of Human Melanocortin 4 Receptor in Saccharomyces cerevisiae. Central European Journal of Biology, 2011. 6: p. 167-175.
http://www.springerlink.com/content/j3p9v10x5007xgg6/
Kopsavilkums
The melanocortin 4 receptor (MC4R) is involved in the regulation of energy homeostasis and is known as one of the major hypothalamic regulators of food intake. Several studies have shown that replacement of aspartic acid at position 126 of the MC4R abolishes the ligand binding. We used the modified yeast Saccharomyces cerevisiae strain MMY28 to functionally express the MC4R and characterise the importance of this amino acid for ligand based activation of the receptor. The efficiency of the functional expression system was estimated by activation with αMSH, ACTH and THIQ and compared with cAMP response in mammalian cells. We generated the library of MC4R mutants randomised at the amino acid position 126. Recombinant MC4R clones were screened for the αMSH induced activity in yeast. From 9 different amino acids obtained only the natural aspartic acid displayed the ligand dependent activity of MC4R. The MC4R variants with glutamic acid and leucine at position 126, however, displayed higher background activity than other amino acid substitutions. The results suggest that the yeast expression system is suitable for screening of the MC4R receptor ligands and that the substitution of aspartic acid at position 126 of MC4R by different amino acids functionally inactivates the receptor.
E.Bisenieks, J.Uldrikis, J.Poikans, M.Petrova, E.Liepinsh and G.Duburs, Reactions of 9-aroyl-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8-octahydroxanthen-1,8-diones with hydrazine and methylhydrazine. Publikācija 2011. gadā nosūtīta uz TetrahedronLetters, kur iereģistrēta
Kopsavilkums
In the reaction of 9-aroyl-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8-octahydroxanthen-1,8-diones with hydrazine and methylhydrazine the derivatives of cinnoline were obtained. In case of methylhydrazine the homolytic bond cleavage of the intermediates take place and the dimer products 4,4'-bis(3-aryl-1,7,7-trimethyl-1,4,5,6,7,8-hexahydrocinnolin-5-ones) were formed.
Identification of Somatostatin Receptor Type 5 (SSTR5) gene polymorphisms associated with acromegaly. Ciganoka D, Balcere I, I Kāpa, R Pečulis, Valtere A, L Ņikitina-Zaķe, Lase I, Schioth H, Pirags V, J Kloviņš , Eur J Endocrinol. 165(4):517-525, 2011
http://www.ncbi.nlm.nih.gov/pubmed/21810856
Kopsavilkums
The aim of this study was to characterize the genetic variance of somatostatin receptor 5 (SSTR5) and investigate the possible correlation of such variants with acromegaly risk and different disease characteristics.
The SSTR5 gene coding region and 2000 bp upstream region was sequenced in 48 patients with acromegaly and 96 control subjects. Further, three single nucleotide polymorphisms (SNPs) were analyzed in the same group of acromegaly patients and in an additional group of 475 age- and sex-matched controls.
In total, 19 SNPs were identified in the SSTR5 gene locus by direct sequencing. Three SNPs (rs34037914, rs169068, and rs642249) were significantly associated with the presence of acromegaly using the initial controls. The allele frequencies were significantly (P<0.01) different between the acromegaly patients and the additional large control group. rs34037914 and rs642249 remained significantly associated with acromegaly after Bonferroni correction and permutation tests (odds ratio (OR)=3.38; 95% confidence interval (CI), 1.78-6.42; P=0.00016 and OR=2.41; 95% CI, 1.41-4.13; P=0.0014 respectively). Haplotype reconstruction revealed two possible risk haplotypes determined by rs34037914 (633T) and rs642249 (1044A) alleles. Both haplotypes were found in significantly higher frequency in acromegaly patients compared with controls (P<0.001). In addition, the 663T allele was significantly associated with a younger age of acromegaly diagnosis (unstandardized regression coefficient β=-10.4; P=0.002), increased body mass index (β=4.1; P=0.004), higher number of adenoma resection (P<0.001) and lack of observable tumor shrinkage after somatostatin analog treatment (P=0.014).
Our results demonstrate a previously undetected strong association of two SSTR5 SNPs with acromegaly. The data also suggest a possible involvement of SSTR5 variants in decreased suppression of GH production and increased tumor proliferation.
Peteris Tretjakovs, Antra Jurka, Inga Bormane, Indra Mikelsone, Karlina Elksne, Gita Krievina, Dace Reihmane, Jurijs Verbovenko, Guntis Bahs. Circulating adhesion molecules, matrix metalloproteinase-9, plasminogen activator inhibitor-1, and myeloperoxidase in coronary artery disease patients with stable and unstable angīna. Clinica Chimica Acta, 413 (2012) 25-29 (PubMed datubāzes žurnāls)
http://www.ncbi.nlm.nih.gov/pubmed/22024218
Kopsavilkums
There are many pathophysiological mechanisms underlying reciprocal relationships between changes in cytokines and insulin resistance in metabolic and cardiovascular disorders. The aim of this study was to evaluate alterations in soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), matrix metalloproteinase-9 (MMP-9), plasminogen activator inhibitor-1 (PAI-1), and myeloperoxidase (MPO) levels, and their relation to insulin resistance in coronary artery disease (CAD) patients with stable and unstable angina (SAP, UAP).
Non-diabetic CAD patients were classified into two groups: 22 patients with SAP and 22 patients with UAP. 22 healthy subjects were selected as controls. The study groups were matched for age and sex. Insulin resistance was evaluated by HOMA-IR method. Serum levels of sICAM-1, sVCAM-1, sE-selectin PAI-1(total), MPO and MMP-9 were quantified by xMAP technology (Luminex-200 analyzer).
Both patient groups demonstrated significantly elevated serum levels of sICAM-1, sE-selectin, PAI-1(total), MPO and MMP-9 (p<0.05) as well as higher IR-HOMA values (p<0.05) than those of healthy controls. The elevation was more pronounced in the UAP group (p<0.01). HOMA-IR was correlated with sICAM-1, PAI-1(total), and MMP-9 (p<0.01).
Our findings show that CAD patients have elevated HOMA-IR values. Furthermore, CAD patients with UAP have higher levels of sICAM-1, sVCAM-1, sE-selectin, MMP-9, PAI-1(total), and MPO than patients with SAP, and there are relationships between three of the above biomarkers: sICAM-1, PAI-1(total), MMP-9 and HOMA-IR.
Peteris Tretjakovs, Antra Jurka, Inga Bormane, Indra Mikelsone, Karlina Elksne, Gita Krievina, Dace Reihmane, Jurijs Verbovenko, Guntis Bahs. Relationship of Neopterin to Increased Vascular Cell Adhesion Molecule-1 and Myeloperoxidase Levels in Unstable Angina. Medicina (Kaunas) - iesniegts 2011.g. jūlijā PubMed datubāzes žurnāls)
http://www.manuscriptmanager.com/mm3/overview.php
Peteris Tretjakovs, Antra Jurka, Inga Bormane, Indra Mikelsone, Karlina Elksne, Gita Krievina, Dace Reihmane, Jurijs Verbovenko, Guntis Bahs. Neopterin, cellular adhesion molecules and myeloperoxidase in patients with stabule and unstable angina pectoris. PROCEEDINGS OF THE LATVIAN ACADEMY OF SCIENCES. Section B, Vol. 65 (2011), No. 3/4 (674/675), pp. 20-30.
http://www.blackwellpublishing.com/aphmeeting/abstract.asp?MeetingID=77…
Kopsavilkums
The aim of the present study was to evaluate differences in serum levels of neopterin, adhesion molecules and myeloperoxidase (MPO) between coronary artery disease and metabolic syndrome (CAD-MetS) patients with stable and unstable angina pectoris (SAP, UAP), and to clarify relationships between neopterin and other biomarkers.
The study included 60 patients with CAD-MetS who were classified into two groups, 30 patients with SAP and 30 patients USP. 20 healthy subjects were selected as controls (C). Serum soluble vascular cell adhesion molecule-1 (sVCAM-1), intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin and MPO levels were measured by Luminex xMAP technology, but serum neopterin concentrations were measured by radioimmunoassay.
Serum levels of neopterin, MPO, sVCAM-1, sICAM-1, and sE-selectin were significantly higher in patients with UAP in comparison with the group of healthy controls (p<0.05). Patients with SAP also had higher levels of these biomarkers than healthy controls (p<0.05), except for sE-selectin. The biomarkers did not differ between the two patient groups, except for MPO, which was significantly higher in the USP group (p<0.05). Neopterin was significantly correlated only with sVCAM-1 (p<0.05).
CAD-Met patients with SAP have more apparent elevations of serum sICAM-1 and sVCAM-1 levels, simultaneously with higher MPO and neopterin concentrations than healthy subjects, but UAP is also associated with more substantial changes in MPO and significantly increased sE-selectin levels. Neopterin has a close correlation only with sVCAM-1.
