DC isoketal-modified proteins activate T cells and promote hypertension

Kirabo, Annet; Fontana, Vanessa; Faria, Ana Paula; Loperena, Roxana; Galindo, Christi L; Wu, Jing; Bikineyeva, Alfiya; Dikalov, Sergey; Xiao, Ling; Chen, Wei; Saleh, Mohamed A.; Trott, Daniel W.; Itani, Hana A.; Vinh, Antony; Amarnath, Venkataraman; Amarnath, Kalyani; Guzik, Tomasz J.; Bernstein, Kenneth E.; Shen, Xiao Z.; Shyr, Yu; Chen, Sheau-Chiann; Mernaugh, Raymond L.; Laffer, Cheryl L.; Elijovich, Fernando; Davies, Sean S.; Moreno, Heitor; Madhur, Meena S; Roberts, L. Jackson; Harrison, David G.

doi:10.1172/jci74084

Cited by 460 publications

(568 citation statements)

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“…Moreover, recently it has been reported that isoketals, which are formed via the isoprostane pathway of lipid peroxidation, activate T cells by modifying dendritic cell proteins. 51 Therefore, it is possible that CYP1B1 might also participate in the generation of isoketals, but this hypothesis needs to be determined.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Thirunavukkarasu

Khan

Song

et al. 2016

The American Journal of Pathology

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Cytochrome P450 (CYP) 1B1 is implicated in vascular smooth muscle cell migration, proliferation, and hypertension. We assessed the contribution of CYP1B1 to angiotensin (Ang) IIeinduced abdominal aortic aneurysm (AAA). Male Apoe À/À /Cyp1b1 þ/þ and Apoe À/À /Cyp1b1 À/À mice were infused with Ang II or its vehicle for 4 weeks; another group of Apoe À/À /Cyp1b1 þ/þ mice was coadministered the CYP1B1 inhibitor 2,3 0 ,4,5 0 -tetramethoxystilbene (TMS) every third day for 4 weeks. On day 28 of Ang II infusion, AAAs were analyzed by ultrasound and ex vivo by Vernier calipers, mice were euthanized, and tissues were harvested. Ang II produced AAAs in Apoe À/À /Cyp1b1 þ/þ mice; mice treated with TMS or Apoe À/À /Cyp1b1 À/À mice had reduced AAAs. Ang II enhanced infiltration of macrophages, T cells, and platelets and increased plateletderived growth factor D, Pdgfrb, Itga2, and matrix metalloproteinases 2 and 9 expression in aortic lesions; these changes were inhibited in mice treated with TMS and in Apoe À/À /Cyp1b1 À/À mice. Oxidative stress resulted in cyclooxygenase-2 expression in aortic lesions. These effects were minimized in Apoe À/À / Cyp1b1 þ/þ mice treated with TMS and in Apoe À/À /Cyp1b1 À/À mice and by concurrent treatment with the superoxide scavenger 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl. CYP1B1 contributed to the development of Ang IIeinduced AAA and associated pathogenic events in mice, likely by enhancing oxidative stress and associated signaling events. Thus, CYP1B1 may serve as a target for therapeutic agents for AAA in males. (Am J Pathol 2016 http://dx

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Section: Discussionmentioning

confidence: 99%

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Thirunavukkarasu

Khan

Song

et al. 2016

The American Journal of Pathology

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“…There is mounting evidence that isolevuglandins form covalent adducts with proteins in various biological milieux, such as in normal and fibrotic lung tissue [69], human retina [70], and dendritic cells [71]. The mechanisms of protein crossing-linking by isolevuglandins have been investigated, and found to occur both by aminal and pyrrole-pyrrole cross-links [72].…”

Section: Isolevuglandinsmentioning

confidence: 99%

“…More recently, a similar approach was used to study the formation of isoketal-lysine-lactam adducts in dendritic cells by stable isotope dilution multiple reaction monitoring mass spectrometry [71]. The ability to identify isolevuglandin adducts in vivo is important to demonstrate the formation of these lipid oxidation products, as free isolevuglandins as cannot be detected in tissues, owing to their very high reactivity with amines [67].…”

Section: Zhu Et Al Incubated Chymotrypsin Cytochrome C β-Lactoglobmentioning

confidence: 99%

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

Sousa

Pitt

Spickett

2017

Free Radical Biology and Medicine

145

105

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The process of lipid oxidation generates a diverse array of small aldehydes and carbonyl-containing compounds, which may occur in free form or esterified within phospholipids and cholesterol esters. These aldehydes mostly result from fragmentation of fatty acyl chains following radical oxidation, and the products can be subdivided into alkanals, alkenals (usually D,β-unsaturated), γ-substituted alkenals and bis-aldehydes.Isolevuglandins are non-fragmented di-carbonyl compounds derived from H 2 -isoprostanes, and oxidation of the ω-3-fatty acid docosahexenoic acid yield analogous 22 carbon neuroketals. Non-radical oxidation by hypochlorous acid can generate D-chlorofatty aldehydes from plasmenyl phospholipids. Most of these compounds are reactive and have generally been considered as toxic products of a deleterious process. The reactivity is especially high for the D,β-unsaturated alkenals, such as acrolein and crotonaldehyde, and for γ-substituted alkenals, of which 4-hydroxy-2-nonenal and 4-oxo-2-nonenal are best Page | 2 known. Nevertheless, in recent years several previously neglected aldehydes have been investigated and also found to have significant reactivity and biological effects; notable examples are 4-hydroxy-2-hexenal and 4-hydroxy-dodecadienal. This has led to substantial interest in the biological effects of all of these lipid oxidation products and their roles in disease, including proposals that HNE is a second messenger or signalling molecule.However, it is becoming clear that many of the effects elicited by these compounds relate to their propensity for forming adducts with nucleophilic groups on proteins, DNA and specific phospholipids. This emphasizes the need for good analytical methods, not just for free lipid oxidation products but also for the resulting adducts with biomolecules. The most informative methods are those utilizing HPLC separations and mass spectrometry, although analysis of the wide variety of possible adducts is very challenging. Nevertheless, evidence for the occurrence of lipid-derived aldehyde adducts in biological and clinical samples is building, and offers an exciting area of future research. AbbreviationsAcr-dG, 1,N2-propanodeoxyguanosine; AGEs, advanced glycation end-product; ALEs, advanced lipoxidation end product; ApoB100, apolipoprotein B100; ApoE, apolipoprotein E; ARP, aldehyde reactive probe; AspN, endoproteinase AspN (flavastacin); βLG, β-lactoglobulin; BHZ, biotin hydrazide; BN-PAGE, blue native polyacrylamide gel

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“…If T cells are actually activated by recognition of a specific antigen in hypertensive animals, what might this antigen be? The study by Kirabo et al in this issue of the JCI now suggests an answer (8).…”

Section: T Cells and Hypertensionmentioning

confidence: 98%

“…Finally, transfer of isoketal-activated DCs raised blood pressure in WT animals that have T cells but not in those lacking them. Cumulatively, the findings of Kirabo and colleagues (8) suggest that peptides derived from isoketal…”

Section: The Role Of Isoketal-activated Dcs In Hypertensionmentioning

confidence: 99%