Vanin-1 Pantetheinase Drives Smooth Muscle Cell Activation in Post-Arterial Injury Neointimal Hyperplasia

The pantetheinase vanin-1 generates cysteamine, which inhibits reduced glutathione (GSH) synthesis. Vanin-1 promotes inflammation and tissue injury partly by inducing oxidative stress, and partly by peroxisome proliferator-activated receptor gamma (PPARγ) expression. Vascular smooth muscle cells (SMCs) contribute to neointimal hyperplasia in response to injury, by multiple mechanisms including modulation of oxidative stress and PPARγ. Therefore, we tested the hypothesis that vanin-1 drives SMC activation and neointimal hyperplasia. We studied reactive oxygen species (ROS) generation and functional responses to platelet-derived growth factor (PDGF) and the pro-oxidant diamide in cultured mouse aortic SMCs, and also assessed neointima formation after carotid artery ligation in vanin-1 deficiency. Vnn1−/− SMCs demonstrated decreased oxidative stress, proliferation, migration, and matrix metalloproteinase 9 (MMP-9) activity in response to PDGF and/or diamide, with the effects on proliferation linked, in these studies, to both increased GSH levels and PPARγ expression. Vnn1−/− mice displayed markedly decreased neointima formation in response to carotid artery ligation, including decreased intima:media ratio and cross-sectional area of the neointima. We conclude that vanin-1, via dual modulation of GSH and PPARγ, critically regulates the activation of cultured SMCs and development of neointimal hyperplasia in response to carotid artery ligation. Vanin-1 is a novel potential therapeutic target for neointimal hyperplasia following revascularization

Functional genetic polymorphisms and female reproductive disorders: Part II—endometriosis

BACKGROUNDEndometriosis has a strong genetic component, and numerous genetic studies have been reported.METHODSWe have systematically reviewed these studies and included 114 in our final selection.RESULTSWe found no consistent evidence linking endometriosis with specific polymorphisms in genes encoding inflammatory mediators, proteins involved in sex steroid metabolism, vascular function and tissue remodelling. Although a number of polymorphisms have been associated with endometriosis in selected populations, the associations have not been independently confirmed, either because only single studies were carried out on these markers/genes or because other studies reported no association. The most solid evidence linking specific polymorphisms to endometriosis came from studies investigating glutathione-S-transferase, a phase II detoxification enzyme. Carriage of the GSTT1 null deletion variant showed consistent association with endometriosis with a 29% increased risk; however, it cannot be excluded that this result was due to publication bias, and this association should be independently confirmed in large-scale, well-designed case\u2013control studies.CONCLUSIONSThe evidence of an association between genetic polymorphisms and endometriosis is weak. Carriage of the GSTT1 null deletion may moderately increase the risk of this disease. We suggest that the methodology of association studies should be improved in order to identify and validate associations in endometriosis

The G2964A 3'-untranslated region polymorphism of the signal transducer and activator of transcription 6 gene is associated with endometriosis in South Indian women.

BACKGROUND: The aim of the study was to test whether the signal transducer and activator of transcription 6 (STAT6) gene influences the risk of developing endometriosis. METHODS: The single-nucleotide polymorphism, G2964A, in the 3'-untranslated region (UTR) of the STAT6 gene was tested for association in a case-control study of 232 affected women and 210 women with no evidence of disease. All the women were infertile, ascertained from the same infertility clinic and of South Indian origin. The genotype frequencies of this polymorphism were compared using PCR and sequencing analysis. RESULTS: There were statistically significant differences in the genotype distributions (P = 0.002) and allele frequencies (P = 0.0002) between the cases and controls, according to codominant, dominant and recessive genotype models. CONCLUSIONS: We report for the first time an association between the STAT6 G2964A 3'-UTR polymorphism and endometriosis in South Indian women. This finding suggests that STAT6 may contribute to disease susceptibility in endometriosis, which carries an extra interest as the gene lies in a region which has been implicated, albeit weakly, in a previous genomewide scan

The G2964A 3'-untranslated region polymorphism of the signal transducer and activator of transcription 6 gene is associated with endometriosis in South Indian women.

BACKGROUND: The aim of the study was to test whether the signal transducer and activator of transcription 6 (STAT6) gene influences the risk of developing endometriosis. METHODS: The single-nucleotide polymorphism, G2964A, in the 3'-untranslated region (UTR) of the STAT6 gene was tested for association in a case-control study of 232 affected women and 210 women with no evidence of disease. All the women were infertile, ascertained from the same infertility clinic and of South Indian origin. The genotype frequencies of this polymorphism were compared using PCR and sequencing analysis. RESULTS: There were statistically significant differences in the genotype distributions (P = 0.002) and allele frequencies (P = 0.0002) between the cases and controls, according to codominant, dominant and recessive genotype models. CONCLUSIONS: We report for the first time an association between the STAT6 G2964A 3'-UTR polymorphism and endometriosis in South Indian women. This finding suggests that STAT6 may contribute to disease susceptibility in endometriosis, which carries an extra interest as the gene lies in a region which has been implicated, albeit weakly, in a previous genomewide scan

The interleukin-6 -174G/C promoter polymorphism is not associated with endometriosis in South Indian women.

OBJECTIVE: To investigate the association of the -174 G/C promoter polymorphism of the interleukin-6 (IL-6) gene with endometriosis in South Indian women. METHODS: The genotype frequencies of the common IL-6 -174 G/C polymorphism were compared in infertility patients with (n = 232) and without (n = 210) endometriosis using polymerase chain reaction (PCR) and sequencing analysis. RESULTS: The genotype frequencies among the cases and controls were G/G 62.9% and 71.9%, G/C 34.1% and 25.2%, and C/C 3.0% and 2.9%. The G and C allele frequencies were 80% and 84.6%, and 20% and 15.4%, respectively. There were no statistically significant differences in the genotype distributions or allele frequencies between the cases and controls (P = .12). CONCLUSIONS: The present study demonstrates no significant association between the IL-6 -174 G/C promoter polymorphism and endometriosis in South Indian women

The interleukin-6 -174G/C promoter polymorphism is not associated with endometriosis in South Indian women.

OBJECTIVE: To investigate the association of the -174 G/C promoter polymorphism of the interleukin-6 (IL-6) gene with endometriosis in South Indian women. METHODS: The genotype frequencies of the common IL-6 -174 G/C polymorphism were compared in infertility patients with (n = 232) and without (n = 210) endometriosis using polymerase chain reaction (PCR) and sequencing analysis. RESULTS: The genotype frequencies among the cases and controls were G/G 62.9% and 71.9%, G/C 34.1% and 25.2%, and C/C 3.0% and 2.9%. The G and C allele frequencies were 80% and 84.6%, and 20% and 15.4%, respectively. There were no statistically significant differences in the genotype distributions or allele frequencies between the cases and controls (P = .12). CONCLUSIONS: The present study demonstrates no significant association between the IL-6 -174 G/C promoter polymorphism and endometriosis in South Indian women

The endothelial nitric oxide synthase Glu298Asp polymorphism is not a risk factor for endometriosis in south Indian women.

OBJECTIVE: To investigate whether the eNOS gene influences the risk of developing endometriosis in south Indian women. STUDY DESIGN: The single nucleotide polymorphism, Glu298Asp, in exon7 of the eNOS gene was tested for association in a case-control study of 232 affected women and 210 women with no evidence of disease. All the women were infertile, ascertained from the same infertility clinic. The genotype frequencies of the polymorphism were compared, using polymerase chain reaction and sequencing analysis. The localization and expression of eNOS in the eutopic endometrium of five cases and four controls was also analyzed using immunohistochemistry and western blotting. RESULTS: No statistically significant differences were observed in the genotype distributions and allele frequencies (p=0.3) between the cases and controls according to codominant, dominant and recessive genotype models. The localization and expression of this protein were similar in the endometrium of cases and controls. CONCLUSION: In the present study we could neither observe a difference in the eNOS expression nor establish an association between the eNOS Glu298Asp exon 7 polymorphism in south Indian women with endometriosis

The vascular endothelial growth factor (VEGF) +405G>C 5'-untranslated region polymorphism and increased risk of endometriosis in South Indian women: a case control study.

BACKGROUND: Vascular endothelial growth factor (VEGF), a major mediator of angiogenesis and vascular permeability, is known to play a key role in the pathophysiology of endometriosis. METHODS AND RESULTS: The single nucleotide polymorphisms, -460C>T and +405G>C, in the 5'-untranslated region of the VEGF gene were tested for association in a case-control study of 215 affected women and 210 women with no evidence of disease. All the women were of South Indian origin and ascertained from the same infertility clinic. The genotype and allele frequencies of the -460C>T polymorphism did not differ significantly between cases and controls. In contrast, the genotype (P = 0.002) and allele (P = 0.001) frequencies of the +405G>C polymorphism showed a significant difference between cases and controls. The +405 GG genotype was found more often in patients with an endometrioma >3 cm compared to controls. The frequency of the -460T/+405C haplotype (P = 0.016) was significantly lower in affected women compared to controls. CONCLUSIONS: The -460T/+405C haplotype in the VEGF gene, which is associated with lower promoter activity, was significantly less common in women with endometriosis than in controls. These data suggest that the +405G allele may influence the likelihood of a woman developing the disease