Objective-LOX-1, a novel lectin-like receptor for oxidized LDL (ox-LDL), is expressed in response to ox-LDL, angiotensin II (Ang II), tumor necrosis factor (TNF)-␣, and other stress stimuli. It is highly expressed in atherosclerotic tissues. Peroxisome proliferator-activated receptor (PPAR)-␥ ligands, such as pioglitazone, exert antiatherosclerotic effects. This study examined the regulation of LOX-1 expression in human coronary artery endothelial cells (HCAECs) by pioglitazone. Methods and Results-Fourth generation HCAECs were treated with ox-LDL, Ang II, or TNF-␣ with or without pioglitazone pretreatment. All 3 stimuli upregulated LOX-1 expression (mRNA and protein). Pioglitazone, in a concentration-dependent manner, reduced LOX-1 expression (PϽ0.01 versus ox-LDL, Ang II, or TNF-␣ alone). Ox-LDL, Ang II, and TNF-␣ each enhanced intracellular superoxide radical generation, and pioglitazone pretreatment reduced superoxide generation (PϽ0.01 versus ox-LDL, Ang II, or TNF-␣). Furthermore, all 3 stimuli upregulated the expression of the transcription factors nuclear factor-B and activator protein-1 (determined by electrophoretic mobility shift assay), and pioglitazone pretreatment reduced this expression (PϽ0.01 versus ox-LDL, Ang II, or TNF-␣). To determine the biological significance of pioglitazone-mediated downregulation of LOX-1, we studied monocyte adhesion to ox-LDL-treated HCAECs. Pioglitazone reduced the adhesion of monocytes to activated HCAECs in a fashion similar to that produced by antisense to LOX-1 mRNA. Key Words: angiotensin Ⅲ atherosclerosis Ⅲ oxidized LDL Ⅲ peroxisome proliferator-activated receptor-␥ Ⅲ tumor necrosis factor-␣ E ndothelial dysfunction elicited by oxidized LDL (ox-LDL) plays a critical role in the pathogenesis of atherosclerosis. 1 Ox-LDL changes the secretory activities of the endothelium and causes it to become dysfunctional. 2 Recent studies have demonstrated that atherosclerotic tissues express large amounts of ox-LDL 3 and all the constituents of the renin-angiotensin system, such as ACE and angiotensin II (Ang II) type I receptors (AT 1 Rs). 4,5 Other work has demonstrated that there is an enhanced expression of cytokines, such as tumor necrosis factor (TNF)-␣, in the atherosclerotic plaque. 6 Ox-LDL, Ang II, and TNF-␣ all induce the expression of adhesion molecules on the endothelial cells, reduce constitutive NO synthase, and facilitate inflammation, a key process in atherogenesis.
Conclusions-TheseScavenger receptors on macrophages and smooth muscle cells are believed to mediate the biological effect of ox-LDL and Ang II. Recent studies show that LOX-1, a novel lectin-like receptor for ox-LDL, facilitates the uptake of ox-LDL and mediates several of its biological effects. 7 LOX-1 mediates ox-LDL-induced apoptosis in endothelial cells and phagocytosis of aged and apoptotic cells. The expression of LOX-1 gene is upregulated by ox-LDL, Ang II, inflammatory cytokines, and shear stress. 7 Other studies from our laboratory have shown a cross talk between ox-LDL and Ang II in t...