COMMENTARIES

Lectin-like Oxidized Low-density Lipoprotein Receptor-1 (LOX-1): a New Promising Target for Therapy of Atherosclerosis-related Diseases

Changping Hu, Abhijit Dandapat, and Jawahar L. Mehta, Department of Internal Medicine and Physiology and Biophysics,
University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System,
Little Rock, AR
Please address correspondence to:
J.L. Mehta, M.D., Ph.D.
Cardiovascular Medicine
University of Arkansas for Medical Sciences
4301 West Markham St., Slot 532
Little Rock, AR 72205-7199
Tel: (501) 296-1401
Fax: (501) 686-6180
E-mail: MehtaJL@uams.edu

Atherogenesis is a complex process initiated by endothelial dysfunction. This early step is followed by deposition of oxidized lipids in monocytes/macrophages, smooth muscle cell proliferation and migration, and an intense inflammatory reaction. Rupture of the soft inflamed atherosclerotic plaque results in exposure of sub-endothelial collagen to platelets and occlusion of the artery. Production of reactive oxygen species (ROS) is also increased in atherosclerotic arteries well beyond the capability of endogenous antioxidants to inactivate them [1]. ROS directly injure endothelium, denature nitric oxide, oxidize lipids, and attract inflammatory cells to the site of injury [2,3]. In keeping with this concept, oxidatively modified LDL (ox-LDL) levels are elevated in patients with unstable atherosclerotic disease [4].

In 1997, Sawamura et al. identified LOX-1 (lectin-like ox-LDL receptor) in bovine aortic endothelial cells [5]. This receptor is responsible for binding and uptake of ox-LDL in endothelial cells [6,7]. The contributory role of LOX-1 in atherogenesis is supported by several lines of evidence [8]: (i) LOX-1 shows a strong activity in binding, internalizing, and degrading ox-LDL; (ii) ox-LDL activates LOX-1 and induces endothelial dysfunction and apoptosis; (iii) besides ox-LDL, other mediators of atherosclerosis, such as angiotensin II, cytokines, sheer stress, and advanced glycation end-products, upregulate LOX-1; (iv) LOX-1 is dynamically upregulated by pro-atherogenic conditions, such as diabetes, hypertension, and dyslipidemia; and (iv) LOX-1 is present in atheroma-derived cells and in human and animal atherosclerotic lesions.

          Besides endothelial cells, LOX-1 is also expressed on smooth muscle cells and monocyte/macrophages [8]. Although the expression level is relatively low, LOX-1 functions as a scavenger receptor, which binds and internalizes ox-LDL, resulting in the transformation of smooth muscle cells and monocyte/macrophages into foam cells. In addition, LOX-1 has also been identified on platelets [9], and plays an important role in platelet aggregation [10] and thrombus formation (unpublished data)

          Recently, we described generation of LOX-1 knockout (KO) mice in which binding of oxLDL to aortic endothelium is reduced and endothelium-dependent vasorelaxation preserved after treatment of mice aorta with oxLDL. This contrasts with the loss of acetylcholine-mediated relaxation in aortic rings from wild-type mice [11]. To address whether endothelial functional preservation might lead to reduction in atherogenesis, we crossed LOX-1 KO mice with LDLR KO mice and fed these mice with 4% cholesterol/10% cocoa butter diet for 18 weeks. Atherosclerosis was found to cover 61 ± 2% of aorta in the LDLR KO mice, but only 36 ± 3% of aorta in the double KO mice. Luminal obstruction and intima thickness were significantly reduced in the double KO mice (versus LDLR KO mice).

Expression of the redox-sensitive transcription factor NF-kB and the inflammatory marker CD68 in LDLR KO mice was increased (versus wild-type mice) in the aortas of LDLR KO mice, but not in the double KO mice. On the other hand, anti-inflammatory cytokine IL-10 expression and superoxide dismutase activity were low in the LDLR KO mice (versus wild-type mice) suggesting loss of anti-inflammatory and anti-oxidant species. Interestingly, LOX-1 deletion abrogated the loss of anti-inflammatory and anti-oxidant moieties in the double KO mice. Endothelial nitric oxide synthase expression which is down-regulated in the atherosclerotic areas was also preserved in the double KO mice. The pro-inflammatory p38 component of MAPK was activated in the LDLR KO mice in keeping with previous observations [12], and LOX-1 abrogation reduced its activation.

          These findings suggest that LOX-1 expression is important in atherogenesis, and its deletion limits atherogenesis despite high cholesterol diet, in large part, by preserving endothelial function and integrity. The LOX-1 activation thus seems to bridge several phenomena related to atherosclerosis, such as endothelial dysfunction, oxidative stress, and inflammation. Our recent data also shows that a major complication of atherosclerosis, myocardial ischemic injury, can also be attenuated by LOX-1 deletion [13]. In keeping with this hypothesis, circulating levels of LOX-1 have been shown to be elevated in patients with acute coronary syndromes [14]. We suggest that LOX-1 may well be a new promising target for prediction, prevention, and treatment of atherosclerosis-related diseases.

References

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