ZAK induces MMP-2 activity via JNK/p38 signals and reduces MMP-9 activity by increasing TIMP-1/2 expression in H9c2 cardiomyoblast cells.
Leucine-zipper and sterile-alpha motif kinase (ZAK) is the key intra-cellular mediator protein in cardiomyocyte hypertrophy induction by transforming growth factor beta 1 (TGF-beta1) which has also been identified as a profibrotic cytokine involved in cardiac fibrosis progression. We hypothesized whether ZAK over-expression causes cardiac scar formation due to the extra-cellular matrix (ECM) degraded enzyme regulation in this paper. Using immuno-histochemical analysis of the human cardiovascular tissue array, we found a positively significant association between ZAK over-expression and myocardial scars. ZAK over-expression in H9c2 cardiomyoblast cells increases the metalloproteinase tissue inhibitor 1/2 (TIMP-1/2) protein level, which reduces matria metalloproteinase-9 (MMP-9) activity and also activates c-JNK N-terminal kinase 1/2 (JNK1/2) and p38 signaling, which induces MMP-2, possibly resulting in cardiac fibrosis. Taken together, ZAK activity inhibition may be a good strategy to prevent the cardiac fibrosis progression.
Cheng
Yi-Chang
YC
Emergency Department, China Medical University Hospital, Taichung, Taiwan.
Kuo
Wei-Wen
WW
Wu
Hsi-Chin
HC
Lai
Tung-Yuan
TY
Wu
Chun-Hsien
CH
Hwang
Jin-Ming
JM
Wang
Wen-Hong
WH
Tsai
Fuu-Jen
FJ
Yang
Jaw-Ji
JJ
Huang
Chih-Yang
CY
Chu
Chun-Hsien
CH
D000818:Animals; D002460:Cell Line; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D011494:Protein Kinases / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases
D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D011494:Protein Kinases; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D048051:p38 Mitogen-Activated Protein Kinases; C542928:Map3k20 protein, rat; D020930:MAP Kinase Kinase Kinases