Role of protein kinase C in geranylgeranylacetone-induced expression of heat-shock protein 72 and cardioprotection in the rat heart.
We recently demonstrated that oral administration of geranylgeranylacetone (GGA), an antiulcer agent, induces heat-shock protein 72 (HSP72) in the rat heart and renders cardioprotection against ischemia/reperfusion injury. However, the signaling pathways remain to be elucidated. The present study tested the hypothesis that oral GGA would activate protein kinase C (PKC), leading to the phosphorylation and translocation of heat-shock factor 1 (HSF1), and thus, promote the expression of HSP72 protein. Rats were classified into four groups: a control (CNT) group (vehicle administration), a GGA group (GGA 200 mg/kg administration), a chelerythrine (CHE)-CNT group (pretreated with intravenous (i.v.) injection of 5 mg/kg CHE before vehicle administration), and a CHE-GGA group (pretreated with CHE before GGA administration). After 24 h administration, oral GGA-induced overexpression of HSP72, increased amount of the phosphorylated form of HSF1 in the nucleus, produced heat-shock element-specific DNA-HSF1 complex, and caused translocation of protein kinase C (PKC)delta, all of which were prevented by pretreatment with CHE. GGA also increased the PKC activity in a particulate fraction, which was prevented by pretreatment with rottlerin, a specific inhibitor of PKCdelta. Isolated-perfused heart experiments revealed that the better functional recovery observed in the GGA group during the reperfusion period following the 20 min of no-flow global ischemia, compared with the CNT group, was abolished by pretreatment with CHE. These results suggest that activation of PKC (translocation of PKCdelta), which primes the phosphorylation of HSF1, plays an essential role in the cardiac overexpression of HSP72 by GGA that leads to cardioprotection.
Yamanaka
Kunitoshi
K
Department of Internal Medicine I, School of Medicine, Oita Medical University, 1-1 Idaigaoka, Hasama, 879-5593, Oita, Japan.
Takahashi
Naohiko
N
Ooie
Tatsuhiko
T
Kaneda
Koji
K
Yoshimatsu
Hironobu
H
Saikawa
Tetsunori
T
D000098:Acetophenones / Q000494:pharmacology; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D001578:Benzopyrans / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism; D010617:Phenanthridines / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014157:Transcription Factors
D000098:Acetophenones; D000470:Alkaloids; D053119:Benzophenanthridines; D001578:Benzopyrans; D004268:DNA-Binding Proteins; D004224:Diterpenes; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C000619709:Hsf1 protein, rat; D007527:Isoenzymes; D010617:Phenanthridines; D014157:Transcription Factors; C085746:rottlerin; C016299:chelerythrine; D011493:Protein Kinase C; C031049:geranylgeranylacetone