Triggering of p38 MAPK and JNK signaling is important for oleanolic acid-induced apoptosis via the mitochondrial death pathway in hypertrophic scar fibroblasts.
Hypertrophic scarring is characterized by collagen overproduction and excessive deposition of extracellular matrix. No consensus arises currently about the best therapeutics to produce complete and permanent improvement of scars with few side effects. In the present study, the mechanism of oleanolic acid (OA)-induced apoptosis in hypertrophic scar fibroblasts (HSFs) was investigated for the first time. OA activated the protein phosphorylation of p38 MAPK and JNK but not ERK. OA did not antagonize the inhibitory effects of SB203580 on p38 MAPK pathway activity but sharply enhanced JNK phosphorylation when HSFs were pretreated with SB203580. Similarly, the inhibition of JNK signal pathway activation by pretreatment with SP600125 facilitated the protein phosphorylation of p38 MAPK caused by OA. Inhibition of p38 MAPK and/or JNK by inhibitors significantly enhanced cell viability and OA only partially depressed the increased cell viability. Moreover, OA increased Bax translocation, MMP loss, mitochondrial cytochrome c and AIF release, Bax and caspase-3 protein expression and the ratio of Bax to Bcl-2, decreased Bcl-2 protein expression, and elevated the mRNA expression of Apaf-1, caspase-9, and capase-3. These results suggest that OA elicits apoptosis through triggering of p38 MAPK and JNK signaling and activation of the mitochondrial death pathway. OA might be a good and useful natural drug against hypertrophic scars.
Department of Pharmacognosy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, PR China; Department of Pharmaceutical Botany, School of Pharmacy, Second Military Medical University, Shanghai, 200433, PR China.
Jian-Yu
JY
Chen
Lei
L
Zhang
Hong
H
Zhang
Li
L
Su
Lu-Ping
LP
Qin
D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D017439:Cicatrix, Hypertrophic / Q000473:pathology*; D045304:Cytochromes c / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D009828:Oleanolic Acid / Q000494:pharmacology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C506592:APAF1 protein, human; D000873:Anthracenes; D053477:Apoptotic Protease-Activating Factor 1; C494826:BAX protein, human; D007093:Imidazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D051028:bcl-2-Associated X Protein; C432165:pyrazolanthrone; D009828:Oleanolic Acid; D045304:Cytochromes c; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; C093642:SB 203580
apoptosis; fibroblast; mitochondria; natural product; signaling pathway