Activation of the 12-lipoxygenase and signal transducer and activator of transcription pathway during neointima formation in a model of the metabolic syndrome.
Insulin resistance (IR) is associated with an increased risk of cardiovascular diseases. The obese Zucker rat (ZR) is a model of IR that shows markedly increased insulin and triglyceride concentrations without major changes in glucose. In this study, we evaluated the response of obese and lean ZR to carotid balloon injury and determined potential mechanisms and treatments. The neointima-to-media ratio of obese ZR was greater than that of lean ZR, starting at 14 days after injury, and persisted until at least day 30. An enhanced inflammatory response to balloon injury in the obese ZR was reflected by significantly higher ED1-positive macrophage cells in the injured vessel wall compared with that in lean ZR at 3, 7, and 14 days after balloon injury. Inflammatory mediators 12-lipoxygenase (12-LO) and STAT4 were studied in neointimal lesions. Expression of 12-LO RNA was increased beginning at day 7 and showed increases of 4.3-fold on day 14 and 7-fold on day 30 in obese ZR compared with lean animals. Staining of phosphorylated STAT4 (PSTAT4), the activated form of STAT4, in lesions from obese ZR was also increased compared with that in leans. We tested the effects of a novel anti-inflammatory agent, lisofylline (LSF), in the obese ZR. LSF markedly reduced neointimal formation in the obese ZR. LSF also reduced monocyte/macrophage infiltration into the vessel wall and the activation of PSTAT4. These studies suggest both the presence of an exaggerated injury response in the insulin-resistant obese ZR model and that inflammation plays a major role in mediating neointimal growth.
Pei
Hong
H
Division of Endocrinology, Department of Internal Medicine, University of Virginia, PO Box 801405, Charlottesville, VA 22908, USA.
Gu
Jiali
J
Thimmalapura
Pushpa-Rekha
PR
Mison
Angeles
A
Nadler
Jerry L
JL
D000800:Angioplasty, Balloon; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002339:Carotid Arteries / Q000201:enzymology / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D053331:Ectodysplasins; D005260:Female; D015870:Gene Expression / Q000235:genetics; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000097:blood; D019394:Ki-67 Antigen / Q000032:analysis; D008055:Lipids / Q000097:blood; D008565:Membrane Proteins / Q000032:analysis; D024821:Metabolic Syndrome / Q000201:enzymology / Q000378:metabolism*; D010431:Pentoxifylline / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D050797:STAT4 Transcription Factor / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000032:analysis; D017539:Tunica Intima / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D053331:Ectodysplasins; D007328:Insulin; D019394:Ki-67 Antigen; D008055:Lipids; D008565:Membrane Proteins; D050797:STAT4 Transcription Factor; D048069:Tumor Necrosis Factors; D001092:Arachidonate 12-Lipoxygenase; C025189:lisofylline; D010431:Pentoxifylline