Introduction. Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the most severe complications of pulmonary embolism (PE), characterized by poor prognosis and insuffcient effectiveness of standard treatment approaches. A small number of representative models of CTEPH make it diffcult to conduct preclinical studies of promising pharmacological substances.Objective – development and validation of the experimental model of CTEPH in rats by embolization of the distal branches of the pulmonary artery with biodegradable microspheres.Material and methods. Male Wistar rats were used for the experiments. Biodegradable microspheres (MS) based on sodium alginate and autologous blood clots (AT) were used as embolizing particles. The animals were divided into groups: control: saline solution was injected 4 times with an interval of 8 days into the tail vein; AT: according to the above protocol, 50 μL of AT was injected; MS was administered intravenously in a volume of 50 μl of MS according to two protocols: MS4: 4 times with an interval of 8 days; MS8: 8 times with an interval of 4 days. After 2 and 6 weeks after the last injection, a histological examination of the lungs was performed; after 6 weeks: echocardiographic study (TTE), right ventricular catheterization (RV) with measurement of right ventricular systolic pressure (RVSP), treadmill test, assessment of serum endothelin1 levels by the immunoassay method.Results. During the experiments, the survival rate in the MS8 group was 50 %. In the other groups, there were no animal losses. According to the treadmill test 6 weeks after the modeling of PE, exercise tolerance was signifcantly reduced in the MC4 and MC8 groups compared with the control group. TTE data indicate a signifcant increase in the diameter of the pulmonary trunk and the right ventricular outflow tract in the MC8 compared with the control and AT. There were signifcant increase in RVSP and the level of endothelin1 compared with the control only in the MS8. After 6 weeks, the index of hypertrophy of vessel wall of the pulmonary artery in the MC4 and MC8 was signifcantly higher compared with the control and AT groups.Conclusion. Based on the use of MS, administered under the MS 8 protocol, a new representative model of CTEPH has been created, which can be used to test promising pharmacological substances.
Recovery of the contractile function of the heart and the regeneration of the myocardium after ischemic injury are contemporary issues in regenerative medicine and cell biology. This study aimed to analyze early transcriptional events in cardiac tissue after infarction and to explore the cell population that can be isolated from myocardial tissue. We induced myocardial infarction in Wistar rats by permanent ligation of the left coronary artery and showed a change in the expression pattern of Notch-associated genes and Bmp2/Runx2 in post-MI tissues using RNA sequencing and RT-PCR. We obtained primary cardiac mesenchymal cell (CMC) cultures from postinfarction myocardium by enzymatic dissociation of tissues, which retained part of the activation stimulus and had a pronounced proliferative potential, assessed using a “xCELLigence” real-time system. Hypoxia in vitro also causes healthy CMCs to overexpress Notch-associated genes and Bmp2/Runx2. Exogenous activation of the Notch signaling pathway by lentiviral transduction of healthy CMCs resulted in a dose-dependent activation of the Runx2 transcription factor but did not affect the activity of the Bmp2 factor. Thus, the results of this study showed that acute hypoxic stress could cause short-term activation of the embryonic signaling pathways Notch and Bmp in CMCs, and this interaction is closely related to the processes of early myocardial remodeling after a heart attack. The ability to correctly modulate and control the corresponding signals in the heart can help increase the regenerative capacity of the myocardium before the formation of fibrotic conditions.
Abstract⎯An association study was performed for genetic polymorphisms in ADRB3 (rs4994) and ADRA2A (rs1800544, rs553668) genes to estimate their effect on quantitative parameters, including glucose, insulin, and HOMA IR index in women from the Tatar population of Russia. It has been shown that CT and CC are associated with metabolic syndrome and increased insulin. It was shown that ADRA2A (rs1800544) gene poly morphism was associated with high levels of insulin and an increased HOMA IR index in GG and GC gen otype carriers. Polymorphic locus rs553668 of gene ADRA2A is associated with increased glucose in CT and TT genotype carriers.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism with poor clinical outcomes. Therapeutic approaches to prevention of fibrotic remodeling of the pulmonary vascular bed in CTEPH are limited. In this work, we tested the hypothesis that Janus kinase 1/2 (JAK1/2) inhibition with ruxolitinib might prevent and attenuate CTEPH in a rat model. CTEPH was induced by repeated embolization of the pulmonary artery with partially biodegradable 180 ± 30 μm alginate microspheres. Two weeks after the last injection of microspheres, ruxolitinib was administered orally at doses of 0.86, 2.58, and 4.28 mg/kg per day for 4 weeks. Prednisolone (1.475 mg/kg, i.m.) was used as a reference drug. Ruxolitinib in all doses as well as prednisolone reduced pulmonary vascular wall hypertrophy. Ruxolitinib at a dose of 2.58 mg/kg and prednisolone reduced vascular wall fibrosis. Prednisolone treatment resulted in decreased right ventricular systolic pressure. Pulmonary vascular resistance was lower in the prednisolone and ruxolitinib (4.28 mg/kg) groups in comparison with the placebo group. The plasma level of brain natriuretic peptide was lower in groups receiving ruxolitinib at doses of 2.58 and 4.28 mg/kg versus placebo. This study demonstrated that JAK1/2 inhibitor ruxolitinib dose-dependently reduced pulmonary vascular remodeling, thereby preventing CTEPH formation in rats.
Aim. The aim of the study was a replicative analysis of the association of polymorphic variants of genes associated with obesity revealed by results of wide-genomic studies (GWAS) with the development of a cluster of metabolic syndrome risk parameters in women of Bashkir and Tatar ethnicity. The polymorphic markers of the following genes were analyzed: SEC16B, FADS1, KCTD15, MAF, MAP2K5, NEGR1, BDNF, TMEM18.
Materials and methods. The study involved 243 women with metabolic syndrome and 298 women without the metabolic syndrome. Amplification of DNA fragments was performed using real-time PCR and TaqMan technique.
Results. We found the association the metabolic syndrome with genetic markers of genes MAF and TMEM18 from Tatar. Protective informative marker of the metabolic syndrome among Tatar and Bashkir was the TT haplotype TMEM18 gene (rs2860323 and rs6548238) (р=0.005 and р=0.001, respectively). We identified the association marker rs2241423 MAP2K5 gene with the level of waist circumference (p=0.003) and with the level of cholesterol (p=0.014), the marker rs11084753 KCTD15 gene with glucose levels after exercise (p=0.002), the level of triglycerides (p=0.003) and HDL (p=0.0008) among Tatar women. We identified the association rs2241423 MAP2K5 gene marker to glycated hemoglobin level (p=0.002) and a marker gene rs174550 FADS1 with triglyceride levels (p=0.02) among Bashkir women.
Conclusion. It can be assumed that the polymorphic variants FADS1, KCTD15, MAF, MAP2K5, TMEM18 genes are an important part of the genetic structure of predisposition to metabolic syndrome and/or to a cluster of clinical and biochemical indicators of the risk of metabolic syndrome.
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