title: Diabetes-induced oxidative stress and low-grade inflammation in porcine coronary arteries.
abstract: BACKGROUND
  Multiple pathways contribute to accelerated coronary atherosclerosis in diabetics, including increased oxidative stress and inflammatory burden. Accordingly, the mechanisms of abnormal formation of reactive oxygen species and the changes in inflammatory gene expression were examined in diabetic coronary arteries.
  
  
  RESULTS
  In pigs with streptozotocin-induced diabetes, superoxide formation was augmented in coronary media and adventitia because of increased NAD(P)H oxidase activity (3 months) accompanied by upregulated expression of its cytosolic subunit, p22phox. Diabetes-induced oxidative stress resulted in the inflammatory response in the adventitia (increased expression of interleukin-6, tumor necrosis factor-alpha, monocyte chemotactic protein-1, vascular cell adhesion molecule-1 [VCAM-1]) and in the media (VCAM-1). To examine the mechanisms of these changes, studies with isolated coronary fibroblasts were undertaken. Advanced glycation end products (AGEs), rather than glucose itself, upregulated expression of interleukin-6, VCAM-1, and monocyte chemotactic protein-1 mRNAs. These results were paralleled by increased interleukin-6 secretion (P<0.01) and augmented leukocyte adhesion to AGE-stimulated coronary cells (P<0.001). AGEs increased expression of phosphorylated forms of mitogen-activated protein kinases in coronary cells (ERK1/2 and JNK) and resulted in redox-sensitive expression of inflammatory genes that was inhibited by several inhibitors of oxidative pathways [NAD(P)H oxidase inhibitors, N-acetylcysteine, and pyrrolidine dithiocarbamate].
  
  
  CONCLUSIONS
  Diabetes increased NAD(P)H oxidase activity and oxidative stress, producing inflammatory responses in porcine coronary media and adventitia. AGEs activated ERK1/2 and JNK signaling pathways and induced the expression of several inflammatory genes in coronary cells in a redox-sensitive manner. These results suggest the involvement of AGEs in the development of accelerated coronary atherosclerosis in diabetes.
authors.affiliation: Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: LiFeng
authors.initials: L
authors.lastname: Zhang
authors.forename: Andrew
authors.initials: A
authors.lastname: Zalewski
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Tomasz
authors.initials: T
authors.lastname: Mazurek
authors.forename: Scott
authors.initials: S
authors.lastname: Cowan
authors.forename: Jack L
authors.initials: JL
authors.lastname: Martin
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Hofmann
authors.forename: Helen
authors.initials: H
authors.lastname: Vlassara
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000209:etiology; D003331:Coronary Vessels / Q000473:pathology* / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D019255:NADPH Oxidases; D018384:Oxidative Stress; D010766:Phosphorylation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013311:Streptozocin; D013481:Superoxides / Q000378:metabolism; D013552:Swine; D017540:Tunica Media / Q000378:metabolism / Q000473:pathology
chemical_list: D017127:Glycation End Products, Advanced; D018836:Inflammation Mediators; D021122:Protein Subunits; D012333:RNA, Messenger; D013481:Superoxides; D013311:Streptozocin; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases