Partial deficiency of HIF-1α stimulates pathological cardiac changes in streptozotocin-induced diabetic mice

Diabetic cardiomyopathy is associated with a number of functional and structural pathological changes such as left ventricular dysfunction, cardiac remodeling, and apoptosis. The primary cause of diabetic cardiomyopathy is hyperglycemia, the metabolic hallmark of diabetes. Recent studies have shown that a diabetic environment suppresses hypoxia-inducible factor (HIF)-1α protein stability and function. The aim of this study was to analyze the functional role of HIF-1α in the development of diabetic cardiomyopathy. We have hypothesized that the partial deficiency of HIF-1α may compromise cardiac responses under diabetic conditions and increase susceptibility to diabetic cardiomyopathy.

Diabetes was induced by streptozotocin in wild type (Wt) and heterozygous Hif1a knock-out (Hif1a+/-) mice. Echocardiographic evaluations of left ventricular functional parameters, expression analyses by qPCR and Western blot, and cardiac histopathology assessments were performed in age-matched groups, diabetic, and non-diabetic Wt and Hif1a+/- mice.

Five weeks after diabetes was established, a significant decrease in left ventricle fractional shortening was detected in diabetic Hif1a+/- but not in diabetic Wt mice. The combination effects of the partial deficiency of Hif1a and diabetes affected the gene expression profile of the heart, including reduced vascular endothelial growth factor A (Vegfa) expression. Adverse cardiac remodeling in the diabetic Hif1a+/- heart was shown by molecular changes in the expression of structural molecules and components of the extracellular matrix.

We have shown a correlation between heterozygosity for Hif1α and adverse functional, molecular, and cellular changes associated with diabetic cardiomyopathy. Our results provide evidence that HIF-1α regulates early cardiac responses to diabetes, and that HIF-1α deregulation may influence the increased risk for diabetic cardiomyopathy.