Abstract 1559: Increased Length Of Hospitalization And Weight Gain In Diabetic Patients Are Associated With induction of HIF1α expression and Higher serum Levels Of Permeability-inducing Growth Factors: Vegf, And Hgf

Abstract

Background- Inflammatory mediators such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) play a critical role in the regulation of vascular permeability, and angiogenesis. We studied the serum levels of several growth factors including VEGF, FGF, and HGF as well as gene expression profiles of genes involved in growth factor signaling in the peripheral blood of patients with diabetes mellitus (DM) and without diabetes mellitus (ND) following cardiopulmonary bypass (CPB) and cardioplegic arrest (C). Methods- Serum for evaluation of growth factors and total RNA for microarray analysis were obtained from the blood samples collected from DM patients (n=8) and matched ND patients (n=8) who underwent coronary artery bypass graft (CABG) or valve procedures; before (pre), 6 hours (6h), and 4 days (4d) after CPB/C. The cytokine panel consisting of growth factors such as VEGF, HGF, FGF, and EGF were quantified in DM and ND patients; pre, 6h, and 4d post-CPB/C using a multiplex cytokine quantification system. cDNA microarray analysis was performed using Affymetrix Genechip U133 plus 2.0 software to assess gene expression of 47,000 genes. Further validation of gene expression was performed by quantitative real-time PCR. Results- Length of hospitalization (9 vs. 6 days post-surgery; p=0.04) and weight gain (6 lbs vs. 2.4 lbs 4d post-surgery; p<0.01) were significantly greater for DM patients when compared to ND patients. VEGF, and HGF were elevated in DM and ND patients; 6h post-CBP/C. The serum levels of these cytokines were elevated significantly in DM patients when compared to ND patients; pre vs. 6h post-CPB/C. In correlation with VEGF protein expression, microarray analysis showed significantly elevated levels of HIF1α mRNA expression (> 4 fold), a critical regulator of hypoxia signaling, 4d after CPB/C exclusively in DM patients. Other transcription factors such as CREB and P300 that directly affect HIF1α expression were also significantly elevated only in DM patients (p<0.01). Conclusion- The unique pattern of gene and protein expression profile of growth factors and their related genes in DM vs. ND patients could be associated with increased edema and weight gain in DM patients after CPB/C.