Published online before print June 23, 2005, doi: 10.1161/01.RES.0000174563.62625.8e
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© 2005 American Heart Association, Inc.
Molecular Medicine |
In Vivo and In Vitro Studies Support That a New Splicing Isoform of OLR1 Gene Is Protective Against Acute Myocardial Infarction
From the Departments of Biopathology and Diagnostic Imaging (R.M., F.V., F.S., F.A., A.F., P.S., G.N.), Neuroscience (S.B., I.F.), Internal Medicine (R.M., F.C., R.L., F.R.), and Experimental Medicine and Biochemical Sciences (S.G., C.F.), University of Tor Vergata, Rome, Italy; the Division of Cardiovascular Medicine (J.M., F.R., G.N.), University of Arkansas for Medical Sciences, Little Rock; and the Center of Excellence for Genomic Risk Assessment in Multifactorial and Complex Diseases (R.M., F.V., F.S., F.A., A.F., P.S. R.L., F.R., G.N.), School of Medicine, University of Tor Vergata, Rome, Italy.
Correspondence to Dr Giuseppe Novelli, Department of Biopathology and Diagnostic Imaging, or Dr Silvia Biocca, Department of Neuroscience, University of Tor Vergata, Via Montpellier 1, Rome, Italy, 00133. Email novelli{at}med.uniroma2.it or biocca@med.uniroma2.it
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), encoded by the OLR1 gene, is a scavenger receptor that plays a fundamental role in the pathogenesis of atherosclerosis. LOX-1 activation is associated with apoptosis of endothelial cells, smooth muscle cells (SMCs), and macrophages. This process is an important underlying mechanism that contributes to plaque instability and subsequent development of acute coronary syndromes. Independent association genetic studies have implicated OLR1 gene variants in myocardial infarction (MI) susceptibility. Because single nucleotide polymorphisms (SNPs) linked to MI are located in intronic sequences of the gene, it remains unclear as to how they determine their biological effects. Using quantitative real-time PCR and minigene approach, we show that intronic SNPs, linked to MI, regulate the expression of a new functional splicing isoform of the OLR1 gene, LOXIN, which lacks exon 5. Macrophages from subjects carrying the "non-risk" disease haplotype at OLR1 gene have an increased expression of LOXIN at mRNA and protein level, which results in a significant reduction of apoptosis in response to oxLDL. Expression of LOXIN in different cell types results in loss of surface staining, indicating that truncation of the C-terminal portion of the protein has a profound effect on its cellular trafficking. Furthermore, the proapoptotic effect of LOX-1 receptor in cell culture is specifically rescued by the coexpression of LOXIN in a dose-dependent manner. The demonstration that increasing levels of LOXIN protect cells from LOX-1 induced apoptosis sets a groundwork for developing therapeutic approaches for prevention of plaque instability.
Key Words: OLR1 • myocardial infarction • LOX-1 • oxLDL • apoptosis
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