Decreased cardiac expression of vascular endothelial growth factor and redox imbalance in murine diabetic cardiomyopathy.
Type 1 diabetes is associated with a unique form of cardiomyopathy that is present without atherosclerosis. Redox imbalance and/or changes in vascular endothelial growth factor (VEGF) expression have been associated with diabetes-related cardiomyopathy. However, the mechanisms of these changes and their interrelationships remain unclear. Using a murine type 1 diabetes model, we tested the hypothesis that alterations in cardiac performance are associated with decreased cardiac microvascular prevalence, as well as downregulation of VEGF isoforms. We also investigated oxidative stress as a contributor to regulate individual VEGF isoforms and microvascular rarefaction. Significant and rapid hyperglycemia was observed at 1 wk post-streptozotocin (STZ) and persisted throughout the 5-wk study. Left ventricular (LV) fractional shortening was reduced at week 1 and 5 post-STZ insult relative to age-matched controls. We also observed the early reduction in E/A ratio at 1 wk. Immunostaining for CD31 and digital image analysis demonstrated a 35% reduction in microvessels/myocardial area, indicative of rarefaction, which was highly correlated with fractional shortening. Furthermore, a significant increase in the prevalence of protein 3-nitrotyrosine was observed in the diabetic cardiac tissue, which was inversely associated with microvascular rarefaction. The expressions of three VEGF isoforms were significantly reduced to different extents. The reduction of VEGF(164) was associated with GSSG accumulation. These data demonstrate that the mouse model of STZ-induced diabetes has hallmark features observed in humans with respect to nonischemic systolic and diastolic performance and microvascular rarefaction, which are associated with changes in VEGF isoform expression and redox imbalance in the myocardium.
Han
Bing
B
Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
Baliga
Reshma
R
Huang
Hong
H
Giannone
Peter J
PJ
Bauer
John Anthony
JA
D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D003326:Coronary Circulation / Q000502:physiology; D048909:Diabetes Complications / Q000378:metabolism* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008833:Microcirculation / Q000502:physiology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D013047:Specific Pathogen-Free Organisms; D013318:Stroke Volume / Q000502:physiology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000502:physiology
D016877:Oxidants; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C002744:3-nitrotyrosine; D014443:Tyrosine; D005978:Glutathione; D019803:Glutathione Disulfide