ABSTRACT
BACKGROUND: Uncoupling protein 2 (UCP2) is critical in regulating energy metabolism. Due to the significant change in energy metabolism of myocardium upon pressure overload, we hypothesize that UCP2 could contribute to the etiology of cardiac hypertrophy. METHODS: Adult male C57BL/6J mice were subjected to pressure overload by using transverse aortic constriction (TAC), and then received genipin (a UCP2 selective inhibitor; 25 mg/kg/d, ip) or vehicle for three weeks prior to histologic assessment of myocardial hypertrophy. ATP concentration, ROS level, and myocardial apoptosis were also examined. A parallel set of experiments was also conducted in UCP2-/- mice. RESULTS: TAC induced left ventricular hypertrophy, as reflected by increased ventricular weight/thickness and increased size of myocardial cell (vs. sham controls). ATP concentration was decreased; ROS level was increased. Apoptosis and fibrosis markers were increased. TAC increased mitochondrial UCP2 expression in the myocardium at both mRNA and protein levels. Genipin treatment attenuated cardiac hypertrophy and the histologic/biochemical changes described above. Hypertrophy and associated changes induced by TAC in UCP2-/- mice were much less pronounced than in WT mice. CONCLUSIONS: Blocking UCP2 expression attenuates cardiac hypertrophy induced by pressure overload.
Subject(s)
Aorta/pathology , Cardiomegaly/prevention & control , Ion Channels/metabolism , Mitochondrial Proteins/metabolism , Adenosine Triphosphate/metabolism , Animals , Cardiomegaly/etiology , Constriction, Pathologic , Ion Channels/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondrial Proteins/genetics , Reactive Oxygen Species/metabolism , Uncoupling Protein 2ABSTRACT
AIM: To investigate the effects of triptolide on proinflammatory factor-induced over-expression of class II major histocompatibility complex (class II MHC), B7-1, B7-2, and intercellular adhesion molecule-1 (ICAM-1) in human proximal tubular epithelial (HKC) cells. METHODS: HKC cells were exposed to both interferon gamma (IFN-gamma, 200 microg/L) and tumor necrosis factor alpha (TNF-alpha, 20 microg/L) and cultured in media containing different concentrations of triptolide for 24 h. Class II MHC, B7-1, B7-2, and ICAM-1 levels in HKC cells were evaluated by flow cytometry. ICAM-1 mRNA level was measured by semi-quantitative RT-PCR method. RESULTS: HKC cells expressed quite high level of ICAM-1 and very low levels of class II MHC, B7-1, and B7-2 molecules. Class II MHC, B7-1, B7-2, and ICAM-1 levels in HKC cells were significantly increased by the costimulation of IFN-gamma and TNF-alpha. Triptolide inhibited the over-expression of class II MHC, B7-1, and B7-2 molecules in a concentration-dependent manner. The up-regulations of ICAM-1 molecules and ICAM-1 mRNA level were not altered by triptolide. CONCLUSION: Triptolide can significantly inhibit proinflammatory factors induced over-expression of class II MHC, B7-1, and B7-2 costimulatory factors in tubular epithelial cells. These results may contribute to the therapeutic effects of triptolide in some renal diseases.
