Hypoxia‐inducible factor 1α is critically involved in metallothionein protection against diabetic cardiomyopathy

Abstract

Previous studies have shown that metallothionein (MT) protects against diabetic cardiomyopathy (DCM) in mice. The current study was undertaken to test the hypothesis that the protective role of MT against DCM is mediated by hypoxia‐inducible factor ‐1 (HIF‐1) pathway leading to an increased angiogenesis and a normalization of glucose metabolism in a MT cardiac specific over‐expression mouse model and a rat embryonic cardiac fibroblast H9c2 cell line. Streptozotocin‐induced diabetes decreased cardiac HK‐II protein level, a HIF target and an important glycolysis enzyme; and cardiac‐specific MT over‐expression relieved this suppression. MT over‐expression increased HK‐II mRNA level nder both non‐diabetic and diabetic conditions. In vitro analysis showed that MT over‐expression increased and normalized the hyperglycemia‐reduced glycolysis. MT over‐expression significantly prevented the diabetes‐induced reduction in angiogenesis. Further studies showed that MT over‐expression increased HIF‐1α mRNA and protein level in diabetic heart and in MT stable over‐expressing H9c2 cells, indicating the transcriptional modulation of HIF‐1α by MT. This study demonstrated that MT increased HIF‐1 transcriptional activity leading to the normalization of glycolysis and angiogenesis in cardiomyocytes under diabetic conditions. Supported by a grant from American Diabetes Association (W.F)