Novel Protective Role for Ubiquitin-Specific Protease 18 in Pathological Cardiac Remodeling.

Ubiquitin-specific protease 18 (USP18), a USP family member, is involved in antiviral activity and cancer inhibition. Although USP18 is expressed in heart, the role of USP18 in the heart and in cardiac diseases remains unknown. Here, we show that USP18 expression is elevated in both human dilated hearts and hypertrophic murine models. Cardiomyocyte-specific overexpression of USP18 in mice significantly blunted cardiac remodeling as evidenced by mitigated myocardial hypertrophy, fibrosis, ventricular dilation, and preserved ejection function, whereas USP18-deficient mice displayed exacerbated cardiac remodeling under the same pathological stimuli. Similar results were observed for in vitro angiotensin II-induced neonatal rat cardiomyocyte hypertrophy. The antihypertrophic effects of USP18 under hypertrophic stimuli were associated with the blockage of the transforming growth factor-ß-activated kinase 1-p38/c-Jun N-terminal kinase 1/2 signaling cascade. Blocking transforming growth factor-ß-activated kinase 1-p38/c-Jun N-terminal kinase 1/2 signaling with a pharmacological inhibitor (5Z-7-oxozeaenol) greatly reversed the detrimental effects observed in USP18-knockout mice subjected to aortic banding. Our data indicate that USP18 inhibits cardiac hypertrophy and postpones cardiac dysfunction during the remodeling process, which is dependent on its modulation of the transforming growth factor-ß-activated kinase 1-p38/c-Jun N-terminal kinase 1/2 signaling axis. Thus, USP18 is a potent therapeutic target for heart failure treatment.

[Prevention and treatment of experimental liver fibrosis in rats by Semen Hoveniae extracts].

OBJECTIVE: To investigate the prevention and treatment of experimental liver fibrosis in rats by Semen Hoveniae extracts (SHE). METHODS: Rats liver fiborsis model was induced by carbon tetrachloride (CCl4). SD rats were randomly divided into six groups: the normal control group, the model control group, the positive control group and the SHE groups. The level of serum procollgan type-III (PC-III), hyaluronic acid (HA), laminin (LN) and liver function were measured, respectively. Liver histological examination was made. RESULTS: SHE could ameliorate CCl4-induced liver fibrosis significantly. The lever of serum PC-III, HA, LN decreased and liver function was improved. The histological examination also demonstrated its anti-fibrotic effect. CONCLUSION: SHE have anti-fibrotic effect on liver in vivo, and may have potential value for clinical use.

[Effects of TIMP-2 gene transfer on atherosclerotic plaque in rabbits].

OBJECTIVE: To evaluate the effects of TIMP-2 local gene transfer on atherosclerotic plaque. METHODS: Atherosclerosis models were induced by denuding femoral artery endothelium plus high lipid diet in rabbits. TIMP-2 gene was transferred locally by balloons eluted with pcDNA3-TIMP-2. RT-PCR and Western blot were performed to verify exogenous genes transfer. MMPs activity in atherosclerotic plaque was evaluated by zymography. HE and VG staining and automatic image analysis system were used for pathological analysis of atherosclerotic femoral arteries. The lumen area of the vessel and the collagen contents in the atherosclerotic plaque were measured. RESULTS: The expression of TIMP-2 gene in pcDNA3-TIMP-2 transferred group was significantly higher than control-vector transferred group at the end of week 2 after operation and reached the peak at the end of week 4. Comparing with the control group, the expression of TIMP-2 protein in treated group was also higher at the end of week 2, 4, and 8 after operation. Correspondingly, the MMP-2 and MMP-9 activities were lower in treated group. The thickness of fibrous cap of atherosclerotic plaque and the amount of collagen of the lesion were increased significantly in treated group compared with the control group, but there were no significant differences in vessel lumen area. CONCLUSION: TIMP-2 gene transfer locally in atherosclerotic plaque could inhibit the activities of MMP-2 and MMP-9 in the lesion, increase the thickness of fibrous cap and the amount of collagen of the lesion, but may have no effect on the degree of the stenosis.