Proteomic and biochemical analyses reveal the activation of unfolded protein response, ERK-1/2 and ribosomal protein S6 signaling in experimental autoimmune myocarditis rat model.
BACKGROUND
To investigate the molecular and cellular pathogenesis underlying myocarditis, we used an experimental autoimmune myocarditis (EAM)-induced heart failure rat model that represents T cell mediated postinflammatory heart disorders.


RESULTS
By performing unbiased 2-dimensional electrophoresis of protein extracts from control rat heart tissues and EAM rat heart tissues, followed by nano-HPLC-ESI-QIT-MS, 67 proteins were identified from 71 spots that exhibited significantly altered expression levels. The majority of up-regulated proteins were confidently associated with unfolded protein responses (UPR), while the majority of down-regulated proteins were involved with the generation of precursor metabolites and energy metabolism in mitochondria. Although there was no difference in AKT signaling between EAM rat heart tissues and control rat heart tissues, the amounts and activities of extracellular signal-regulated kinase (ERK)-1/2 and ribosomal protein S6 (rpS6) were significantly increased. By comparing our data with the previously reported myocardial proteome of the Coxsackie viruses of group B (CVB)-mediated myocarditis model, we found that UPR-related proteins were commonly up-regulated in two murine myocarditis models. Even though only two out of 29 down-regulated proteins in EAM rat heart tissues were also dysregulated in CVB-infected rat heart tissues, other proteins known to be involved with the generation of precursor metabolites and energy metabolism in mitochondria were also dysregulated in CVB-mediated myocarditis rat heart tissues, suggesting that impairment of mitochondrial functions may be a common underlying mechanism of the two murine myocarditis models.


CONCLUSIONS
UPR, ERK-1/2 and S6RP signaling were activated in both EAM- and CVB-induced myocarditis murine models. Thus, the conserved components of signaling pathways in two murine models of acute myocarditis could be targets for developing new therapeutic drugs or methods aimed at treating enigmatic myocarditis.
Seoul Center, Korea Basic Science Institute, Sungbuk-gu, Seoul 136-713, Republic of Korea.
Joo Hee
JH
Chung
Hee Jung
HJ
Choi
Soo Young
SY
Kim
Kwan Soo
KS
Hong
Soo Kee
SK
Min
Myung Hee
MH
Nam
Chan Wha
CW
Kim
Young Ho
YH
Koh
Jong Bok
JB
Seo
D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004770:Enterovirus / Q000502:physiology; D005786:Gene Expression Regulation; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics* / Q000378:metabolism; D009205:Myocarditis / Q000378:metabolism* / Q000473:pathology; D040901:Proteomics; D051381:Rats; D011917:Rats, Inbred Lew; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D056811:Unfolded Protein Response / Q000502:physiology
D038601:Ribosomal Protein S6; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3