title: Impaired Nrf2 regulation of mitochondrial biogenesis in rostral ventrolateral medulla on hypertension induced by systemic inflammation.
abstract: Oxidative stress in rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons reside, is involved in the development of hypertension under systemic inflammation. Mitochondrial dysfunction contributes to tissue oxidative stress. In this study, we sought to investigate whether hypertension developed under systemic inflammation is attributable to impaired mitochondrial biogenesis in RVLM. In normotensive Sprague-Dawley rats, intraperitoneal infusion of a low dose Escherichia coli lipopolysaccharide (LPS) for 7 days promoted a pressor response, alongside a decrease in mitochondrial DNA (mtDNA) copy number, reductions in protein expression of nuclear DNA-encoded transcription factors for mitochondrial biogenesis, including mitochondrial transcription factor A (TFAM) and nuclear factor erythroid-derived 2-like 2 (Nrf2), and suppression of nuclear translocation of the phosphorylated Nrf2 (p-Nrf2) in RVLM neurons; all of which were abrogated by treatment with intracisternal infusion of an interleukin-1β (IL-1β) blocker, IL-1Ra, or a mobile mitochondrial electron carrier, coenzyme Q10 (CoQ10). Microinjection into RVLM of IL-1β suppressed the expressions of p-Nrf2 and TFAM, and evoked a pressor response; conversely, the Nrf2 inducer, tert-butylhydroquinone, lessened the LPS-induced suppression of TFAM expression and pressor response. At cellular level, exposure of neuronal N2a cells to IL-1β decreased mtDNA copy number, increased protein interaction of Nrf2 to its negative regulator, kelch-like ECH-associated protein 1 (Keap1), and reduced DNA binding activity of p-Nrf2 to Tfam gene. Together these results indicate that defect mitochondrial biogenesis in RVLM neurons entailing redox-sensitive and IL-1β-dependent suppression of TFAM because of the increase in the formation of Keap1/Nrf2 complex, reductions in nuclear translocation of the activated Nrf2 and its binding to the Tfam gene promoter may underlie hypertension developed under the LPS-induced systemic inflammation.
authors.affiliation: Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
authors.forename: Kay L H
authors.initials: KLH
authors.lastname: Wu
authors.affiliation: Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Wu
authors.affiliation: Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
authors.forename: Yung-Mei
authors.initials: YM
authors.lastname: Chao
authors.affiliation: Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
authors.forename: Chun-Ying
authors.initials: CY
authors.lastname: Hung
authors.affiliation: Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan. Electronic address: jchan@adm.cgmh.org.tw.
authors.forename: Julie Y H
authors.initials: JYH
authors.lastname: Chan
mesh_terms: D000818:Animals; D056915:DNA Copy Number Variations / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000235:genetics* / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics* / Q000378:metabolism; D007679:Kidney Medulla / Q000187:drug effects / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D050983:NF-E2 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D001678:Organelle Biogenesis; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D053583:Interleukin-1beta; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D008070:Lipopolysaccharides; D050983:NF-E2 Transcription Factor; C489030:Tfam protein, rat; D014157:Transcription Factors
keywords: Hypertension; Inflammation; Mitochondrial biogenesis; Mitochondrial transcription factor A; Nrf2; Oxidative stress; Rostral ventrolateral medulla