Abstract
In human, damage repair after acute cardiac injury involves a series of complex tissue remodeling events to replace damaged tissue with a fibrotic scar. In contrast, zebrafish heart can undertake complete regeneration after severe injury. This implies the possibility of resolving human cardiac fibrosis by learning from the regulatory mechanisms during zebrafish heart regeneration. Previous studies have shown that cardiomyocyte-specific overexpression of transglutaminase-2 (TGM2) will induce ventricular remodeling in transgenic vertebrates. Therefore, this study hypothesized that Tgm2 may be a critical regulator of extracellular matrix (ECM) remodeling during zebrafish heart regeneration. To investigate this hypothesis, we performed data mining by microarray analysis. We found that tgm2b gene expression was significantly up-regulated after cardiac cryoinjury in adult zebrafish. We next verified that Tgm2’s enzymatic activity increased accordingly after cryoinjury. To study the loss-of-function effect, we used a potent TGM2 inhibitor ERW1041E to treat the zebrafish after cardiac injury. AFOG staining showed that the deposition of collagen in the wounded region was reduced when Tgm2 activity was inhibited. We also found that the expression levels of col1a1a and tgfb1a would decrease collectively by Tgm2 inhibition. Moreover, loss of Tgm2 activity might affect the protein expression of fibronectin. In conclusion, Tgm2 could regulate the production of ECM proteins during zebrafish heart regeneration, consequently, Tgm2 and its regulatory mechanism might be a therapeutic target for cardiac fibrosis.