Oxidoreductase, morphogenesis, extracellular matrix, and calcium ion-binding gene expression in streptozotocin-induced diabetic rat heart

Pulmonary, Critical Care and Sleep Division, Department of Medicine, Louis Stokes Cleveland Department of Veterans Affairs Medical Center and Case Western Reserve University, Cleveland, Ohio Submitted 27 March 2007 ; accepted in final form 8 June 2007 Diabetes has far-ranging effects on cardiac structure and function. Previous gene expression studies of the heart in animal models of type 1 diabetes concur that there is altered expression of genes involved in lipid and protein metabolism, but they diverge with regard to expression changes involving many other functional groups of genes of mechanistic importance in diabetes-induced cardiac dysfunction. To obtain additional information about these controversial areas, genome-wide expression was assessed using microarrays in left ventricle from streptozotocin-diabetic and normal rats. There were 261 genes with statistically significant altered expression of at least ±1.5-fold, of which 124 were increased and 137 reduced by diabetes. Gene ontology assignment testing identified several statistical significantly overrepresented groups among genes with altered expression, which differed for increased compared with reduced expression. Relevant gene groups with increased expression by diabetes included lipid metabolism ( P < 0.001, n = 13 genes, fold change 1.5 to 14.6) and oxidoreductase activity ( P < 0.001, n = 17, fold change 1.5 to 4.6). Groups with reduced expression by diabetes included morphogenesis ( P < 0.00001, n = 28, fold change –1.5 to –5.1), extracellular matrix ( P < 0.02, n = 9, fold change –1.5 to –3.9), cell adhesion ( P < 0.05, n = 10, fold change –1.5 to –2.7), and calcium ion binding ( P < 0.01, n = 13, fold change –1.5 to –3.0). Array findings were verified by quantitative PCR for 36 genes. These data combined with previous findings strengthen the evidence for diabetes-induced cardiac gene expression changes involved in cell growth and development, oxidoreductase activity, and the extracellular matrix and also point out other gene groups not previously identified as being affected, such as those involved in calcium ion homeostasis. oxidoreductase activity; cell growth Address for reprint requests and other correspondence: E. van Lunteren, Pulmonary 111J (W), Cleveland VA Medical Center, 10701 East Blvd., Cleveland, OH 44106 (e-mail: exv4{at}cwru.edu )