PKCbeta regulates ischemia/reperfusion injury in the lung.
Activation of PKCbetaII is associated with the response to ischemia/reperfusion (I/R), though its role, either pathogenic or protective, has not been determined. In a murine model of single-lung I/R, evidence linking PKCbeta to maladaptive responses is shown in the following studies. Homozygous PKCbeta-null mice and WT mice fed the PKCbeta inhibitor ruboxistaurin subjected to I/R displayed increased survival compared with controls. In PKCbeta-null mice, phosphorylation of extracellular signal-regulated protein kinase-1 and -2 (ERK1/2), JNK, and p38 MAPK was suppressed in I/R. Expression of the immediate early gene, early growth response-1 (Egr-1), and its downstream target genes was significantly increased in WT mice in I/R, particularly in mononuclear phagocytes (MPs), whereas this expression was attenuated in PKCbeta-null mice or WT mice fed ruboxistaurin. In vitro, hypoxia/reoxygenation-mediated induction of Egr-1 in MPs was suppressed by inhibition of PKCbeta, ERK1/2, and JNK, but not by inhibition of p38 MAPK. These findings elucidate key roles for PKCbetaII activation in I/R by coordinated activation of MAPKs (ERK1/2, JNK) and Egr-1.
Fujita
Tomoyuki
T
Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Asai
Tomohiro
T
Andrassy
Martin
M
Stern
David M
DM
Pinsky
David J
DJ
Zou
Yu Shan
YS
Okada
Morihito
M
Naka
Yoshifumi
Y
Schmidt
Ann Marie
AM
Yan
Shi-Fang
SF
D000818:Animals; D017353:Gene Deletion; D007511:Ischemia / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D055370:Lung Injury; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism
D016328:NF-kappa B; D018808:Transcription Factor AP-1; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D020928:Mitogen-Activated Protein Kinases