Circulation. 2003;108:472-478
Published online before print July 14, 2003, doi: 10.1161/01.CIR.0000080378.96063.23
Published online before print July 14, 2003, doi: 10.1161/01.CIR.0000080378.96063.23
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(Circulation. 2003;108:472.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Diabetes-Induced Oxidative Stress and Low-Grade Inflammation in Porcine Coronary Arteries
From the Departments of Surgery (L.Z., Y.L., T.M., S.C., Y.S.) and Medicine (A.Z.), Thomas Jefferson University, Philadelphia, Pa; GlaxoSmithKline (A.Z.), King of Prussia, Pa; Division of Cardiology (J.L.M.), Bryn Mawr Hospital, Bryn Mawr, Pa; and Division of Experimental Diabetes and Aging (S.M.H., H.V.), Mount Sinai School of Medicine, New York, NY.
Correspondence to Yi Shi, MD, PhD, Department of Surgery, Thomas Jefferson University, Suite 623, 1025 Walnut St, Philadelphia, PA 19107. E-mail yi.shi{at}mail.tju.edu
Received January 16, 2003; revision received April 10, 2003; accepted April 11, 2003.
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.
Methods and 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-
, 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.
Key Words: diabetes mellitus • inflammation • atherosclerosis
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