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. 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, p22 phox . 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 (PϽ0.01) and augmented leukocyte adhesion to AGEstimulated coronary cells (PϽ0.001). 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

Endothelial Dysfunction

“…Moreover, hyperglycemia leads to advanced glycation end products (AGE), which were shown to quench NO and impair endothelial function, as evidenced by inhibition of advanced glycosylation with aminoguanidine (83). AGE induce ROS and promote vascular inflammation, with enhanced expression of interleukin-6, VCAM-1, and MCP-1 (84). This turns into a vicious circle in diabetic nephropathy, because in renal failure, clearance of AGE is delayed, which further promotes vascular and renal injury (85).…”

Atherosclerotic Calcification: Wnt Is the Hint

“…The latter has been demonstrated in atherosclerotic lesions, particularly in vascular myofibroblasts and endothelium 93. BMP2 expression is activated by pathogenic stimuli, such as tumor necrosis factor‐α,94 oxidized lipids,94 and hyperglycemia95, 96 More important, BMP2 has been demonstrated to regulate osteogenic programs contributing to VC 55, 62. One of the main ways in which BMP2 regulates osteogenic gene expression programs is through the induction of transcription factor Msx2, which controls craniofacial mineralization 97.…”

Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals

“…In medial, intimal, and valvular calcification, immune responses initiated by oxidized LDL (6) contribute to low-grade vascular inflammation with upregulation of TNF-α (7) and bone morphogenetic protein 2 (BMP2) (8). BMP2 expression is activated by TNF-α (9), oxidized lipids (9), and hyperglycemia (7,10) in vascular myofibroblasts and endothelium. BMP2 is necessary for osteogenic differentiation of mesenchymal cells (11); via Smaddependent signals, BMP2 upregulates osteogenic (e.g., Msx2, Dlx5, Osterix [Osx]) and chondro-osteogenic (Runx2/Cbfa1, Sox9) transcription factors in mineralizing mesenchymal progenitors (12).…”