Abstract
Nitric oxide and secondary oxides of nitrogen react with unsaturated fatty acids such as linoleic acid to yield oxidized and nitrated products. Fatty acid nitroalkene derivatives, (e.g. nitrolinoleate [LNO 2]) are produced by oxidative inflammatory reactions, detected clinically, display potent electrophilic reactivity and induce post-translational protein modifications that mediate adaptive inflammatory signaling responses. LNO 2 signaling was examined in lung epithelial cells because the alveolar compartment is a rich site for the transduction of redox and inflammatory reactions. LNO 2 did not directly induce Ca 2+ influx in cultured lung epithelial cells, but inhibited bradykinin-induced Ca 2+ influx in a cGMP-independent manner. In contrast, LNO 2 activated MAP kinase (Erk1/2) by a mechanism independent of bradykinin. It was hypothesized that these unique responses were transduced by activation of different protein kinase C isotypes, supported by the observation that LNO 2-mediated inhibition of Ca 2+ influx was blocked by the non-selective PKC inhibitors chelerythine chloride and calphostin C, but not by the calcium dependent "classic" PKC inhibitor Gö6976. Western blot analysis showed that atypical PKCζ was activated by LNO 2 stimulation, with PKCζ and Erk activation also demonstrated in primary culture of human lung type II cells. Addition of pseudotypical PKCζ substrate peptide reversed LNO 2-mediated induction of Ca 2+ influx and MAP kinase activation. Finally, the electrophilic nature of LNO 2 resulted in a novel mode of PKCζ activation, covalent adduction of the enzyme. In summary, LNO 2 mediated signaling in lung type II epithelial cells occurs via a unique pathway involving PKCζ.
| Original language | English |
|---|---|
| Pages (from-to) | 366-372 |
| Number of pages | 7 |
| Journal | Nitric Oxide - Biology and Chemistry |
| Volume | 25 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 30 Oct 2011 |
| Externally published | Yes |
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Keywords
- Calcium mobilization
- Nitrated lipids
- Protein kinase C
- Pulmonary epithelial cell
- Signal transduction
ASJC Scopus subject areas
- Biochemistry
- Clinical Biochemistry
- Cancer Research
- Physiology
Cite this
Atypical PKCζ transduces electrophilic fatty acid signaling in pulmonary epithelial cells. / Guo, Chang Jiang; Schopfer, Francisco J.; Gonzales, Linda; Wang, Ping; Freeman, Bruce A.; Gow, Andrew J.
In: Nitric Oxide - Biology and Chemistry, Vol. 25, No. 3, 30.10.2011, p. 366-372.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Atypical PKCζ transduces electrophilic fatty acid signaling in pulmonary epithelial cells
AU - Guo, Chang Jiang
AU - Schopfer, Francisco J.
AU - Gonzales, Linda
AU - Wang, Ping
AU - Freeman, Bruce A.
AU - Gow, Andrew J.
PY - 2011/10/30
Y1 - 2011/10/30
N2 - Nitric oxide and secondary oxides of nitrogen react with unsaturated fatty acids such as linoleic acid to yield oxidized and nitrated products. Fatty acid nitroalkene derivatives, (e.g. nitrolinoleate [LNO 2]) are produced by oxidative inflammatory reactions, detected clinically, display potent electrophilic reactivity and induce post-translational protein modifications that mediate adaptive inflammatory signaling responses. LNO 2 signaling was examined in lung epithelial cells because the alveolar compartment is a rich site for the transduction of redox and inflammatory reactions. LNO 2 did not directly induce Ca 2+ influx in cultured lung epithelial cells, but inhibited bradykinin-induced Ca 2+ influx in a cGMP-independent manner. In contrast, LNO 2 activated MAP kinase (Erk1/2) by a mechanism independent of bradykinin. It was hypothesized that these unique responses were transduced by activation of different protein kinase C isotypes, supported by the observation that LNO 2-mediated inhibition of Ca 2+ influx was blocked by the non-selective PKC inhibitors chelerythine chloride and calphostin C, but not by the calcium dependent "classic" PKC inhibitor Gö6976. Western blot analysis showed that atypical PKCζ was activated by LNO 2 stimulation, with PKCζ and Erk activation also demonstrated in primary culture of human lung type II cells. Addition of pseudotypical PKCζ substrate peptide reversed LNO 2-mediated induction of Ca 2+ influx and MAP kinase activation. Finally, the electrophilic nature of LNO 2 resulted in a novel mode of PKCζ activation, covalent adduction of the enzyme. In summary, LNO 2 mediated signaling in lung type II epithelial cells occurs via a unique pathway involving PKCζ.
AB - Nitric oxide and secondary oxides of nitrogen react with unsaturated fatty acids such as linoleic acid to yield oxidized and nitrated products. Fatty acid nitroalkene derivatives, (e.g. nitrolinoleate [LNO 2]) are produced by oxidative inflammatory reactions, detected clinically, display potent electrophilic reactivity and induce post-translational protein modifications that mediate adaptive inflammatory signaling responses. LNO 2 signaling was examined in lung epithelial cells because the alveolar compartment is a rich site for the transduction of redox and inflammatory reactions. LNO 2 did not directly induce Ca 2+ influx in cultured lung epithelial cells, but inhibited bradykinin-induced Ca 2+ influx in a cGMP-independent manner. In contrast, LNO 2 activated MAP kinase (Erk1/2) by a mechanism independent of bradykinin. It was hypothesized that these unique responses were transduced by activation of different protein kinase C isotypes, supported by the observation that LNO 2-mediated inhibition of Ca 2+ influx was blocked by the non-selective PKC inhibitors chelerythine chloride and calphostin C, but not by the calcium dependent "classic" PKC inhibitor Gö6976. Western blot analysis showed that atypical PKCζ was activated by LNO 2 stimulation, with PKCζ and Erk activation also demonstrated in primary culture of human lung type II cells. Addition of pseudotypical PKCζ substrate peptide reversed LNO 2-mediated induction of Ca 2+ influx and MAP kinase activation. Finally, the electrophilic nature of LNO 2 resulted in a novel mode of PKCζ activation, covalent adduction of the enzyme. In summary, LNO 2 mediated signaling in lung type II epithelial cells occurs via a unique pathway involving PKCζ.
KW - Calcium mobilization
KW - Nitrated lipids
KW - Protein kinase C
KW - Pulmonary epithelial cell
KW - Signal transduction
UR - http://www.scopus.com/inward/record.url?scp=80053916796&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053916796&partnerID=8YFLogxK
U2 - 10.1016/j.niox.2011.07.003
DO - 10.1016/j.niox.2011.07.003
M3 - Article
C2 - 21871968
AN - SCOPUS:80053916796
VL - 25
SP - 366
EP - 372
JO - Nitric Oxide - Biology and Chemistry
JF - Nitric Oxide - Biology and Chemistry
SN - 1089-8603
IS - 3
ER -