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Abstract: Under hypobaric hypoxia, antioxidant defenses of the heart are stressed by the enhanced production of ROS. Mammalian heart acclimatizes to hypoxia through altered gene expression, which we studied in murine heart exposed to 10h of acute hypobaric hypoxia (AHH), equivalent to 15000ft, using cDNA arrays. Functional classification of genes with a ⩾2-fold change revealed a number of pro-oxidants like Cyba, Xdh, Txnip, Ppp1r15b and antioxidants like Cat, Gpx1, Mt1, Mgst1. Interestingly, the protein level of Cyba, a subunit of NADPH oxidase, was markedly decreased in AHH exposed heart, suggesting the involvement of some stress response pathways. The AHH exposure also caused a significant reduction (50%) in the level of GSH (P <0.05). The present study provides a retrospective insight on the cellular antioxidant defense mechanisms under AHH. [Copyright &y& Elsevier]

Abstract: Nitric oxide (NO) plays critical role in endothelial dysfunction and oxidative stress in COPD, pointing to the significance of endothelial nitric oxide synthase gene (eNOS) variants. We investigated the association of −786T/C, −922A/G, 4B/4A, and 894G/T polymorphisms of eNOS with the disease and its impact on nitrite and malonaldehyde levels in 190 COPD patients and 134 healthy controls, all smokers. The −786C, −922G and 4A alleles were significantly over-represented in patients (p =0.02, p =0.02, and p =0.03, respectively). The haplotypes, −786C:4A, 4A:894G, −786C:894G, and −786C:4A:894G were significantly over-represented in patients (p <0.0001, p =0.02, p =0.02, and p <0.0001, respectively), whereas, haplotypes, −786T:4B, 4B:894G, −786T:894G, and −786T:4B:894G were significantly under-represented in the patients (p <0.0001). The patients had significantly increased levels of nitrite (p =0.003) and malonaldehyde (p <0.0001). Combination of genotypes containing −786C and 4A alleles were greater in patients (p ⩽0.05), and these combinations associated with decreased FEV1 value and nitrite level (p =0.03 and p =0.04, respectively) and with increased malonaldehyde levels (p =0.02). The eNOS −786C, −922G, and 4A alleles, these alleles associated haplotypes and genotype combinations were over-represented in patients. The variants and their combinations of four polymorphisms of eNOS contribute to disturbed pulmonary function and oxidative stress in COPD. [Copyright &y& Elsevier]

Abstract: Background: Cigarette smoke stimulates airway epithelial cells to release pro-inflammatory cytokines which influence various inflammation-related genes, including COX2, whereas p53 expression is known to alter in such a condition. Since both the genes share several common physiological functions including inflammation and oxidative stress, we investigated within gene and gene–gene interactions towards susceptibility to the disease. Method: In a prospective gene-association study we conducted PCR-RFLP for genotyping the COX2 −765G/C and 8473T/C and p53 72Pro/Arg polymorphisms in 229 COPD patients and 147 healthy controls. Results: The −765GC+CC genotypes of COX2 and Pro/Pro+Pro/Arg genotypes of p53 were prevalent in patients with significant odds ratio, 2.05 and 2.30, respectively (p =0.001; p =0.009, respectively), as a consequence, the −765C and 72Pro alleles were prevalent (p ≤0.001). Individually, the 8473T/C polymorphism did not associate with the disease (p =NS), however, it did in the haplotype −765C:8473C, which was significantly higher in patients (p <0.0001). Based on its prevalence, the three alleles were identified as risk-alleles in patients. The combinations of the genotypes containing 3, 4 and 5 risk alleles of the 3 polymorphisms were significantly over-represented in patients, whereas, the genotypes combinations containing 0, 1 and 2 risk alleles were significantly higher in controls (p =0.0004). The pairwise gene–gene interactions validated prevalence of risk-alleles associated pairing of genotypes such as the Pro/Pro+ Pro/Arg with −765GC+−765CC in patients (p =0.01). Conclusion: The prevalence of COX2 and p53 risk-alleles contributes towards susceptibility to the disease. [Copyright &y& Elsevier]