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.