Streptozotocin-induced changes in cardiac gene expression in the absence of severe contractile dysfunction

Diabetes mellitus alters energy substrate metabolism and gene expression in the heart. It is not known whether the changes in gene expression are an a daptive or maladaptive process. To answer this question, we determined both the time-course and the extent of the alteration of gene expession induced by insulin-deficient diabetes. Transcript analysis with real-time quantita tive polymerase chain reaction (PCR) was performed in rat hearts 1 week (ac ute group) or 6 months (chronic group) after administration of streptozotoc in (55 mg/kg). In the acute group, insulin-dependent diabetes induced a 55- 70% decrease of both glucose transporter 1 (GLUT1) and GLUT4 transcripts, a slight decrease of liver-specific carnitine palmitoyltransferase I (CPT I) , and no change in muscle-specific CPT I. The uncoupling protein UCP-3 incr eased three-fold, with no change in UCP-2. These metabolic alterations were accompanied by an isoform switching from the normally expressed alpha myos in heavy chain (MHC) to the fetal isoform beta MHC mRNA, by a 50% decrease of cardiac alpha-actin mRNA, a 30% decrease of the sarcoplasmic Ca+ +-ATPas e mRNA, and a 50% decrease of muscle creatine kinase (P<0.01 v controls). A ll genomic changes were also present in the chronic group. Genomic markers of ventricular dysfunction [tumor necrosis factor alpha (TNF-alpha), induci ble nitric oxide synthase, cyclo-oxygenase-2] were not affected by chronic diabetes. In both groups, there were no changes in resting left ventricular function by echocardiography, Conclusion: the heart adapts to insulin-defi cient diabetes by a rapid and simultaneous response of multiple genes invol ved in cardiac metabolism and function. This genomic adaptation resembles t he adaptation of cardiac hypertrophy, remains stable over time, and does no t lead to major contractile dysfunction. (C) 2000 Academic Press.