title: DC isoketal-modified proteins activate T cells and promote hypertension.
abstract: Oxidative damage and inflammation are both implicated in the genesis of hypertension; however, the mechanisms by which these stimuli promote hypertension are not fully understood. Here, we have described a pathway in which hypertensive stimuli promote dendritic cell (DC) activation of T cells, ultimately leading to hypertension. Using multiple murine models of hypertension, we determined that proteins oxidatively modified by highly reactive γ-ketoaldehydes (isoketals) are formed in hypertension and accumulate in DCs. Isoketal accumulation was associated with DC production of IL-6, IL-1β, and IL-23 and an increase in costimulatory proteins CD80 and CD86. These activated DCs promoted T cell, particularly CD8+ T cell, proliferation; production of IFN-γ and IL-17A; and hypertension. Moreover, isoketal scavengers prevented these hypertension-associated events. Plasma F2-isoprostanes, which are formed in concert with isoketals, were found to be elevated in humans with treated hypertension and were markedly elevated in patients with resistant hypertension. Isoketal-modified proteins were also markedly elevated in circulating monocytes and DCs from humans with hypertension. Our data reveal that hypertension activates DCs, in large part by promoting the formation of isoketals, and suggest that reducing isoketals has potential as a treatment strategy for this disease.
authors.forename: Annet
authors.initials: A
authors.lastname: Kirabo
authors.forename: Vanessa
authors.initials: V
authors.lastname: Fontana
authors.forename: Ana P C
authors.initials: AP
authors.lastname: de Faria
authors.forename: Roxana
authors.initials: R
authors.lastname: Loperena
authors.forename: Cristi L
authors.initials: CL
authors.lastname: Galindo
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Alfiya T
authors.initials: AT
authors.lastname: Bikineyeva
authors.forename: Sergey
authors.initials: S
authors.lastname: Dikalov
authors.forename: Liang
authors.initials: L
authors.lastname: Xiao
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Saleh
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Trott
authors.forename: Hana A
authors.initials: HA
authors.lastname: Itani
authors.forename: Antony
authors.initials: A
authors.lastname: Vinh
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Amarnath
authors.forename: Kalyani
authors.initials: K
authors.lastname: Amarnath
authors.forename: Tomasz J
authors.initials: TJ
authors.lastname: Guzik
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Bernstein
authors.forename: Xiao Z
authors.initials: XZ
authors.lastname: Shen
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.forename: Sheau-chiann
authors.initials: SC
authors.lastname: Chen
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Mernaugh
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Laffer
authors.forename: Fernando
authors.initials: F
authors.lastname: Elijovich
authors.forename: Sean S
authors.initials: SS
authors.lastname: Davies
authors.forename: Heitor
authors.initials: H
authors.lastname: Moreno
authors.forename: Meena S
authors.initials: MS
authors.lastname: Madhur
authors.forename: Jackson
authors.initials: J
authors.lastname: Roberts
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
mesh_terms: D000368:Aged; D000447:Aldehydes / Q000737:chemistry; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D049109:Cell Proliferation; D015331:Cohort Studies; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000473:pathology*; D007249:Inflammation; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*
chemical_list: D000447:Aldehydes; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; D015850:Interleukin-6; D013481:Superoxides; D000804:Angiotensin II; D010100:Oxygen