Abstract
The role of caspase-6 in heart disease is not well understood, particularly with respect to cardiac arrhythmia. Also, the function of syndecan-1 in the stimulation of inflammation or a regenerative response after cardiac injury is unclear. Leptin receptor-deficient (C57BL/KS-leprdb/leprdb) mice were used in the present study. In addition to developing type 2 diabetes, they also develop initial- and end-stage cardiac arrhythmia after 5 and 8 months, respectively. The initial and end-stage arrhythmias were confirmed through progressive variations in the PP intervals observable in electrocardiograms. Histopathological images of the cardiac tissue exhibited scattered and loosened cardiac cells at the initial stage of cardiac arrhythmia, whereas tissue hardness and extensive structural changes in cardiomyocytes were evident at the end stage. At the molecular level, the progressive upregulation of caspase-6 was observed as the cardiac arrhythmia progressed. In the initial stage of arrhythmia, immunohistochemistry revealed that caspase-6 was expressed at the surface of cardiac cells, suggesting that caspase-6 targeted the extracellular matrix, leading to a loosening of the cardiac tissue structure. In the end stage of cardiac arrhythmia, caspase-6 expression was abundant in the cytoplasm, as well as at the cell surface, suggesting that caspase-6 may have cleaved intermediate filaments, paving the way for cellular morphological changes and apoptosis. Notably, syndecan-1 was upregulated 5.8-fold in the initial stage of cardiac arrhythmia, but downregulated at the end stage. Syndecan-1 may restrict the expression of caspase-6 in the initial stage of cardiac arrhythmia, while its downregulation at the end stage may allow destructive changes via caspase-6 overexpression. Furthermore, the knockdown of syndecan-1 using small interfering RNA enhanced the expression of caspase-6 in the cardiac tissue by factors of 1.8 and 1.2 at the initial and end stages of cardiac arrhythmia, respectively, compared with that in non-silenced cardiac tissue. Therefore, it may be concluded that syndecan-1 plays a major role in the regulation of caspase-6 during the pathological stages of cardiac arrhythmia.