Beneficial effect of taurine treatment against doxorubicin-induced cardiotoxicity in mice.

Though the administration of taurine is clinically efficacious against heart failure, the mechanism underlying its cardioprotection remains to be established. To provide information on the mechanism, we examined the effects of taurine on doxorubicin (DOX)-induced cardiotoxicity, with an emphasis on ROS generation and cardiac gene inhibition. Oral administration of taurine (3% w/v in tap water) dramatically reduced the mortality rate in both the acute or sub-acute toxic models of DOX toxicity. It was shown that taurine prevented DOX-induced oxidative stress as determined from cardiac glutathione content. Interestingly, Northern blot analysis revealed that DOX altered cardiac gene expression, including that of alpha-myosin heavy chain, ventricular myosin light chain-2 isoform and brain natriuretic peptide, an effect partially ameliorated by taurine treatment. In conclusion, taurine suppresses ROS generation and regulates gene expression in the DOX treated heart.

Taurine depletion caused by knocking out the taurine transporter gene leads to cardiomyopathy with cardiac atrophy.

The sulfur-containing beta-amino acid, taurine, is the most abundant free amino acid in cardiac and skeletal muscle. Although its physiological function has not been established, it is thought to play an important role in ion movement, calcium handling, osmoregulation and cytoprotection. To begin examining the physiological function of taurine, we generated taurine transporter- (TauT-) knockout mice (TauTKO), which exhibited a deficiency in myocardial and skeletal muscle taurine content compared with their wild-type littermates. The TauTKO heart underwent ventricular remodeling, characterized by reductions in ventricular wall thickness and cardiac atrophy accompanied with the smaller cardiomyocytes. Associated with the structural changes in the heart was a reduction in cardiac output and increased expression of heart cardiac failure (fetal) marker genes, such as ANP, BNP and beta-MHC. Moreover, ultrastructural damage to the myofilaments and mitochondria was observed. Further, the skeletal muscle of the TauTKO mice also exhibited decreased cell volume, structural defects and a reduction of exercise endurance capacity. Importantly, the expression of Hsp70, ATA2 and S100A4, which are upregulated by osmotic stress, was elevated in both heart and skeletal muscle of the TauTKO mice. Taurine depletion causes cardiomyocyte atrophy, mitochondrial and myofiber damage and cardiac dysfunction, effects likely related to the actions of taurine. Our data suggest that multiple actions of taurine, including osmoregulation, regulation of mitochondrial protein expression and inhibition of apoptosis, collectively ensure proper maintenance of cardiac and skeletal muscular structure and function.

Expression of taurine transporter is regulated through the TonE (tonicity-responsive element)/TonEBP (TonE-binding protein) pathway and contributes to cytoprotection in HepG2 cells.

In hypertonic environment, taurine accumulates in cells via activation of TauT (taurine transporter) as an adaptive regulation. Recent studies revealed that TonE (tonicity-responsive element)/TonEBP (TonE-binding protein) pathway regulated the expression of various molecules which protect cells against hypertonic stress. In the present study, we investigated the osmoregulatory mechanisms of TauT expression. TauT was up-regulated at both functional and transcriptional levels in HepG2 under hypertonic condition. The TonE site was identified in the promoter region of TauT gene. Reporter gene assay revealed that promoter activity was increased under hypertonic conditions, whereas deletion or mutation of TonE sequence abolished the induction of the promoter activity in response to hypertonicity. By using the reporter gene plasmids containing a TonE site of TauT promoter (p2xTonE-Luc), it was demonstrated that a TonE site was sufficient for the hypertonicity-mediated activation of TauT promoter. Importantly, co-transfection of TauT promoter gene plasmid with wild-type TonEBP expression vector enhanced promoter activity under isotonic conditions, whereas dominant-negative TonEBP abrogated the TauT promoter activity induced by hypertonicity. Finally, treatment with taurine prevented HepG2 cells from cell death induced by hypertonic medium. These findings suggested that induction of TauT by hypertonicity is mediated by the activation of the TonE/TonEBP pathway and confers resistance to hypertonic stress.

Transplantation of hepatocytes cultured on hydroxyapatite into Nagase analbuminemia rats.

Rat hepatocytes were seeded in porous hydroxyapatite (HA) disks for hepatocyte transplantation to Nagase analbuminemic rat (NAR). To increase the cell density in the HA, cell suspension in the tube containing the disks were centrifuged down. The centrifugation increased the viable cell number in HA disk approximately 4-fold over the static method. The HA disks were intraperitoneally transplanted into NARs and harvested three weeks after the transplantation. Angiogenesis with no obvious inflammatory reaction was found inside the pore areas of HA. The ectopic transplantation well supported the viability of hepatocytes seeded in HA disks evidenced by significant increases in the host rats' serum albumin level as time passed after the transplantation.