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Publication : Activation of HIF-1 by metallothionein contributes to cardiac protection in the diabetic heart.

First Author  Xue W Year  2012
Journal  Am J Physiol Heart Circ Physiol Volume  302
Issue  12 Pages  H2528-35
PubMed ID  22523246 Mgi Jnum  J:188657
Mgi Id  MGI:5441402 Doi  10.1152/ajpheart.00850.2011
Citation  Xue W, et al. (2012) Activation of HIF-1 by metallothionein contributes to cardiac protection in the diabetic heart. Am J Physiol Heart Circ Physiol 302(12):H2528-35
abstractText  Metallothionein (MT) protects against heavy metal-induced cellular damage and may participate in other fundamental physiological and pathological processes, such as antioxidation, proliferation, and cell survival. Previously, we have shown that elevation of MT by transgene or by induction with zinc protects the heart against diabetic cardiomyopathy by mechanisms such as antidiabetes-induced oxidative stress and inactivation of glycogen synthase kinase-3, which mediates glucose metabolism. We also reported that MT overexpression rescued the diabetic-induced reduction of hypoxia-inducible factor (HIF)-1alpha, which plays an important role in glucose utilization and angiogenesis. Here, we showed that overexpression of MT increased hexokinase (HK)-II expression under control conditions and attenuated diabetes-decreased HK-II expression. Glycolytic flux assay demonstrated that MT increased glycolysis output in high glucose-containing media-cultured H9c2 cells. The diabetes-induced reduction in cardiac capillaries was also attenuated by MT overexpression. Furthermore, MT induction significantly increased HIF-1 expression under both control and diabetic conditions. Moreover, in the present study, we demonstrated that MT-enhanced HIF-1alpha activity is likely through a mechanism of protein nuclear translocation. These results suggest that MT induces HIF-1alpha expression, leading to increased HK-II in the diabetic heart.
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