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Impaired Homocysteine Metabolism Associated with High Plasma Interleukin-17A Levels, a Pro-Atherogenic Marker, in an Endogamous Population of North India.

ABSTRACT: Background:Impaired homocysteine metabolism (IHM; hyperhomocysteinemia) has been linked with many complex disorders like cardiovascular diseases and immunological disturbances. However, studies understanding IHM in light of pro- and anti- atherogeneic markers like Interleukin-17A & -10 (IL-17A & IL-10) and Forkhead box p3 (Foxp3, a master transcription factor) are scarce. Aim:In our present study, we aimed to understand the relation of IHM with plasma IL-17A and IL-10 levels and Foxp3 mRNA expression in peripheral blood mononuclear cells (PBMCs) from an endogamous population (Jats of Haryana, North India) with high prevalence of IHM without the concurrence of significant adverse cardiovascular outcomes. Methods:Forty (40) clinically healthy individuals, unrelated up to first cousins, were recruited and were subjected to demographic, physiological and anthropometric profiling, followed by intravenous blood sample collection (fasting) and lipid profiling. Plasma homocysteine levels were estimated and individuals with homocysteine levels ? 15umol/L and <15umol/L were categorized as the impaired homocysteine metabolism group (IHM, n=30) and normal homocysteine metabolism group (NHM, n=10) respectively. Plasma folate and vitamin B12 and MTHFR C677T (methylenetetrahydrofolate reductase) polymorphism were detected. Relative mRNA expression of Foxp3 in PBMCs (normalized to 18S) was quantitated using SyBR green technology. Plasma IL-10 & 17 levels were estimated by ELISA assays. Results and Conclusions:None of the physiological, anthropometric and lipid variables were different between the two groups. Foxp3 mRNA expression levels were relatively lower, and plasma IL-10 levels were found to be comparable among IHM and NHM group. However, significantly higher IL-17A levels and relatively high LDL cholesterol levels were present in the IHM group as compared with NHM. Our findings suggest that the Jats of Haryana, North India, exhibiting high levels of homocysteine, might also carry the high IL-17A -pro-atherogenic marker, suggesting an increasing burden of pre-morbid condition. This apparently does not reach to significant mortality/morbidity attributed to the counter action or balancing act of IL-10 (an anti-atherogenic marker). This further suggests environment-influenced epigenetic control mechanisms of the targeted genes in the present population.

SUBMITTER: Kaur L

PROVIDER: S-EPMC6200300 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Impaired Homocysteine Metabolism Associated with High Plasma Interleukin-17A Levels, a Pro-Atherogenic Marker, in an Endogamous Population of North India.

Kaur Lovejeet L Garg Priyanka Rani PR Ghosh Pradeep Kumar PK Saraswathy Kallur Nava KN

Ethnicity & disease 20181018 4

<h4>Background</h4>Impaired homocysteine metabolism (IHM; hyperhomocysteinemia) has been linked with many complex disorders like cardiovascular diseases and immunological disturbances. However, studies understanding IHM in light of pro- and anti- atherogeneic markers like Interleukin-17A & -10 (IL-17A & IL-10) and Forkhead box p3 (Foxp3, a master transcription factor) are scarce.<h4>Aim</h4>In our present study, we aimed to understand the relation of IHM with plasma IL-17A and IL-10 levels and F ...[more]

PMID: 30405296

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Project description:ObjectiveAtherosclerosis is characterized by frequent communication between infiltrating leukocytes and vascular cells, through chemokine and cytokine networks. Interleukin-17C (IL-17C) is detectable within atherosclerotic lesions; however, the potential involvement of this cytokine has not been examined. Thus, we sought to investigate the role of IL-17C in atherosclerosis.Approach and resultsThe expression of IL-17 cytokines was profiled within aortas of apolipoprotein E double knockout (Apoe(-/-)) mice, and Il17c expression was elevated. Flow cytometry experiments revealed a major population of aortic IL-17C-producing smooth muscle cells. Next, we generated Il17c(-/-)Apoe(-/-) mice and demonstrated that atherosclerotic lesion and collagen content was diminished within Western diet-fed Il17c(-/-)Apoe(-/-) aortas and aortic roots in comparison to Apoe(-/-) controls. Smooth muscle cells and fibroblasts were mainly responsible for the reduced Col1A1 expression in the aorta of Il17c(-/-)Apoe(-/-) mice. Importantly, IL-17C-treated Apoe(-/-) aortas showed upregulated Col1A1 expression ex vivo. Il17c(-/-)Apoe(-/-) mice displayed a proportional reduction in aortic macrophages, neutrophils, T cells, T helper 1 cells, and T regulatory cells, without corresponding changes in the peripheral immune composition. Examination of aortic IL-17A(+) T-cell receptor γδ T cells and Th17 cells demonstrated a stark reduction in the percentage and number of these subsets within Il17c(-/-)Apoe(-/-) versus Apoe(-/-) mice. Explanted 12-week Western diet-fed Apoe(-/-) aortas treated with IL-17C resulted in the induction of multiple vascular chemokines and cytokines. Th17 cells demonstrated attenuated migration toward supernatants from cultures of Il17c(-/-)Apoe(-/-) smooth muscle cells, and short-term homing experiments revealed diminished recruitment of Th17 cells to the aorta of Il17c(-/-)Apoe(-/-) recipients.ConclusionsSmooth muscle cell-derived IL-17C plays a proatherogenic role by supporting the recruitment of Th17 cells to atherosclerotic lesions.

Project description:Genetic or nutritional deficiencies in homocysteine (Hcy) metabolism lead to hyperhomocysteinemia (HHcy) and cause endothelial dysfunction, a hallmark of atherosclerosis. In addition to Hcy, related metabolites accumulate in HHcy but their role in endothelial dysfunction is unknown. Here, we examine how Hcy-thiolactone, N-Hcy-protein, and Hcy affect gene expression and molecular pathways in human umbilical vein endothelial cells. We used microarray technology, real-time quantitative polymerase chain reaction, and bioinformatic analysis with PANTHER, DAVID, and Ingenuity Pathway Analysis (IPA) resources. We identified 47, 113, and 30 mRNAs regulated by N-Hcy-protein, Hcy-thiolactone, and Hcy, respectively, and found that each metabolite induced a unique pattern of gene expression. Top molecular pathways affected by Hcy-thiolactone were chromatin organization, one-carbon metabolism, and lipid-related processes [-log(P value) = 20-31]. Top pathways affected by N-Hcy-protein and Hcy were blood coagulation, sulfur amino acid metabolism, and lipid metabolism [-log(P value)] = 4-11; also affected by Hcy-thiolactone, [-log(P value) = 8-14]. Top disease related to Hcy-thiolactone, N-Hcy-protein, and Hcy was 'atherosclerosis, coronary heart disease' [-log(P value) = 9-16]. Top-scored biological networks affected by Hcy-thiolactone (score = 34-40) were cardiovascular disease and function; those affected by N-Hcy-protein (score = 24-35) were 'small molecule biochemistry, neurological disease,' and 'cardiovascular system development and function'; and those affected by Hcy (score = 25-37) were 'amino acid metabolism, lipid metabolism,' 'cellular movement, and cardiovascular and nervous system development and function.' These results indicate that each Hcy metabolite uniquely modulates gene expression in pathways important for vascular homeostasis and identify new genes and pathways that are linked to HHcy-induced endothelial dysfunction and vascular disease.

Project description:BackgroundAnthropogenic air pollution has been implicated in aberrant changes of DNA methylation and homocysteine increase (>15μM/L). Folate (<3 ng/mL) and vitamin B12 (<220 pg/mL) deficiencies also reduce global DNA methylation via homocysteine increase. Although B-vitamin supplements can attenuate epigenetic effects of air pollution but such understanding in population-specific studies are lacking. Hence, the present study aims to understand the role of air pollution, homocysteine, and nutritional deficiencies on methylation.MethodsWe examined cross-sectionally, homocysteine, folate, vitamin B12 (chemiluminescence) and global DNA methylation (colorimetric ELISA Assay) among 274 and 270 individuals from low- and high- polluted areas, respectively, from a single Mendelian population. Global DNA methylation results were obtained on 254 and 258 samples from low- and high- polluted areas, respectively.ResultsSignificant decline in median global DNA methylation was seen as a result of air pollution [high-0.84 (0.37-1.97) vs. low-0.96 (0.45-2.75), p = 0.01]. High homocysteine in combination with air pollution significantly reduced global DNA methylation [high-0.71 (0.34-1.90) vs. low-0.93 (0.45-3.00), p = 0.003]. Folate deficient individuals in high polluted areas [high-0.70 (0.37-1.29) vs. low-1.21 (0.45-3.65)] showed significantly reduced global methylation levels (p = 0.007). In low polluted areas, despite folate deficiency, if normal vitamin B12 levels were maintained, global DNA methylation levels improved significantly [2.03 (0.60-5.24), p = 0.007]. Conversely, in high polluted areas despite vitamin B12 deficiency, if normal folate status was maintained, global DNA methylation status improved significantly [0.91 (0.36-1.63)] compared to vitamin B12 normal individuals [0.54 (0.26-1.13), p = 0.04].ConclusionsHigh homocysteine may aggravate the effects of air pollution on DNA methylation. Vitamin B12 in low-polluted and folate in high-polluted areas may be strong determinants for changes in DNA methylation levels. The effect of air pollution on methylation levels may be reduced through inclusion of dietary or supplemented B-vitamins. This may serve as public level approach in natural settings to prevent metabolic adversities at community level.

Dataset Information

Impaired Homocysteine Metabolism Associated with High Plasma Interleukin-17A Levels, a Pro-Atherogenic Marker, in an Endogamous Population of North India.

Publications

Impaired Homocysteine Metabolism Associated with High Plasma Interleukin-17A Levels, a Pro-Atherogenic Marker, in an Endogamous Population of North India.

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