title: Dietary nitrite attenuates oxidative stress and activates antioxidant genes in rat heart during hypobaric hypoxia.
abstract: The nitrite anion represents the circulatory and tissue storage form of nitric oxide (NO) and a signaling molecule, capable of conferring cardioprotection and many other health benefits. However, molecular mechanisms for observed cardioprotective properties of nitrite remain largely unknown. We have evaluated the NO-like bioactivity and cardioprotective efficacies of sodium nitrite supplemented in drinking water in rats exposed to short-term chronic hypobaric hypoxia. We observed that, nitrite significantly attenuates hypoxia-induced oxidative stress, modulates HIF-1α stability and promotes NO-cGMP signaling in hypoxic heart. To elucidate potential downstream targets of nitrite during hypoxia, we performed a microarray analysis of nitrite supplemented hypoxic hearts and compared with both hypoxic and nitrite supplemented normoxic hearts respectively. The analysis revealed a significant increase in the expression of many antioxidant genes, transcription factors and cardioprotective signaling pathways which was subsequently confirmed by qRT-PCR and Western blotting. Conversely, hypoxia exposure increased oxidative stress, activated inflammatory cytokines, downregulated ion channels and altered expression of both pro- and anti-oxidant genes. Our results illustrate the physiological function of nitrite as an eNOS-independent source of NO in heart profoundly modulating the oxidative status and cardiac transcriptome during hypoxia.
authors.affiliation: Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organisation, Timarpur, Delhi, India.
authors.forename: Manjulata
authors.initials: M
authors.lastname: Singh
authors.forename: Aditya
authors.initials: A
authors.lastname: Arya
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Kalpana
authors.initials: K
authors.lastname: Bhargava
authors.forename: Niroj Kumar
authors.initials: NK
authors.lastname: Sethy
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D019587:Dietary Supplements; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D000860:Hypoxia / Q000178:diet therapy / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009573:Nitrites / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D000975:Antioxidants; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009573:Nitrites; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D006152:Cyclic GMP