Abstract 356: Effect of Long-Term Diet-Induced Hyperglycemia and Hyperlipidemia on Placenta Growth Factor Expression in Mouse Heart

Abstract

Arteriogenesis (collateral artery remodeling) is a vital adaptation of the vasculature in response to occlusion which serves to improve O2 and nutrient delivery to distal tissue, thereby decreasing risk of tissue damage due to ischemia. Stimulation of arteriogenesis would be highly beneficial in diabetics, who are especially prone to develop ischemic cardiovascular disease. However, arteriogenesis is suppressed in diabetes by an undefined mechanism. Placenta growth factor (PLGF) is a key arteriogenic factor; thus, we hypothesized that decreased PLGF levels might contribute to impaired arteriogenesis in diabetes. To test this hypothesis, we utilized three mouse models of long term (6 mo) diet-induced metabolic dysfunction: hyperglycemic + hyperlipidemic (high fat fed C57BL/6; HG/HL, n=7), hyperlipidemic (low fat fed ApoE-/-; HL, n=5) and extremely hyperlipidemic (high fat fed ApoE-/-; EXHL, n=12). A normoglycemic + normolipidemic control group (low fat fed C57BL/6; CONT, n=9) was also studied. Both males and females were studied to identify gender differences. Mouse phenotype was confirmed by plasma cholesterol assay, intraperitoneal glucose tolerance testing, and body weight. Cardiac PLGF gene expression was decreased in both male and female EXHL (~50%, p<0.01 and ~42%, p=0.09 respectively), compared to HL. PLGF mRNA was also decreased in male (~43%, p=0.06) but not female HG/HL, compared to CONT (n=5). This decrease was specific to PLGF, as mRNA for VEGFR1 (PLGF receptor) and the related growth factor VEGF-A was not affected by diet. We previously showed that PLGF is upregulated by low, physiological levels of hydrogen peroxide in vitro, suggesting that reactive oxygen species (ROS) signaling may be important in regulating PLGF. Since oxidative stress occurs in both hyperglycemia and hyperlipidemia, and arteriogenesis is known to be subject to a “redox window,” the inhibition of PLGF expression we observed may be mediated by oxidative stress. Plasma isoprostane levels confirmed that oxidative stress existed in HG/HL, HL, and EXHL compared to CONT. We conclude that hyperlipidemia is a key metabolic parameter influencing PLGF expression in cardiac tissue. Further studies to identify the role of oxidative stress in PLGF expression are needed.