Cardiovascular disease has been the leading therapeutic category for over two decades growing in value from $60 billion in 1997 to $351.8 billion in 2003, a trend that will continue (see our feature The cardiovascular report). Coronary heart disease is by far the leading cause of deaths from cardiovascular disease. Of the 12 million or so Americans with coronary heart disease, some 1 million suffer new or recurrent myocardial infarctions each year.

Central to the etiology of myocardial infarction as well as many other cardiovascular diseases is atherosclerosis a condition which affects nearly 174 million individuals in the major pharmaceutical markets in 2000. Atherogenic progression occurs as low-density lipoprotein (LDL), a plasma lipoprotein particle whose lipid component includes cholesterol and triglycerides, accumulates within the arterial wall. Once there, the lipids in LDL are chemically modified and oxidized contributing to the growth of plaques. Statins, inhibitors of HMG-CoA reductase, a rate limiting step in the synthesis of endogenous cholesterol, currently represent the primary pharmacological approach to the treatment of atherosclerosis and continues to drive the majority of sales of anti-atherosclerosis therapies. By 2008, total sales of anti-atherosclerosis therapies will have grown to US$13.7billion and a number of novel approaches are being developed to occupy this expanding market.

Inflammation and plaque instability are overlapping features of atherosclerosis and therapeutic agents that target these aspects of cardiovascular disease are attracting much attention. Local inflammation is characterized by the presence of macrophages, foam cells and T cells which all promote neointimal growth through the expression of cytokines and growth factors, especially in the context of hypercholesterolemia. This active inflammatory process promotes the formation of unstable "vulnerable" atherosclerotic plaque. Unstable plaques rupture under the influence of mediators secreted by the inflammatory cells and possibly macrophage apoptosis thereby activating the thrombotic process that leads to acute cardiovascular events such as myocardial infarction, stroke and limb ischemia.

The elevated plasma and tissue levels of oxidized low-density lipoprotein (OxLDL) plays a particularly important role in the entire process of atherogenesis. OxLDL elicits endothelial dysfunction, favoring generation of reactive oxygen species, inhibition of nitric oxide synthesis, and enhancement of monocyte adhesion to activated endothelial cells. In addition, OxLDL is involved in inducing smooth muscle cell migration proliferation, and are avidly ingested by macrophages, resulting in foam cell formation. The pro-apoptotic nature of OxLDL has also been suggested to contribute to plaque instability as it is cytotoxic to vascular endothelial cells, smooth muscle cells and macrophages.

Increased levels of OxLDL relate to plaque instability in human coronary atherosclerotic lesions, while on the other hand the human OLR1 gene coding for the OxLDL receptor LOX-1 (also known as ORL1; oxidized LDL-receptor 1) is overexpressed in humans and animal atherosclerotic lesions. Moreover single nucleotide polymorphisms (SNPs) in introns 4 and 5 of OLR1 have recently been associated with increased risk of myocardial infarction.

In their recent Circulation Research article highlighted in this editorial, Mango et al report on the possible functional consequence of SNPs of OLR1. This group identified 2 ORL1 transcripts in mRNA from human monocyte derived macrophages. One of these products corresponded to the full-length transcript while the other lacked exon 5 and was termed it LOXIN. LOXIN was predicted to code a protein that lacks 2/3 of the lectin-like domain of LOX-1, a region that is important for OxLDL binding. Both isoforms were detected in several cell types (endothelial cells, fibroblasts, and smooth muscle cells), and tissues (heart, kidney and brain).

Having identified the two isoforms of ORL1 the Italian group then proceeded to demonstrate that the OLR1/LOXIN mRNA ratio was 33% higher in human monocyte-derived macrophages of subjects homozygous for the risk haplotype compared with homozygous for the non-risk haplotype. This suggests that the SNPs may result in reduced expression of LOXIN. Correspondingly, a relative increase in the amount of LOXIN was found in cells derived from subjects homozygous for the non-risk haplotype. This suggests a negative link between levels of LOXIN mRNA and protein expression and the incidence of myocardial infarction in humans.