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LOX-1 Transcription

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Abstract

The importance of the lectin-like oxidized LDL receptor (LOX-1) gene in cardiovascular and other diseases is slowly being revealed. LOX-1 gene expression appears to be a “canary in a coal mine” for atherogenesis, being strongly up-regulated early on in a number of cell types when they are activated, and predicting the sites of future disease. From this early time point the LOX-1 protein often participates in the disease process itself. While gene/protein expression can be regulated on a multiplicity of levels, the most basic and important mode of regulation is usually transcriptional. There are very few studies on the transcriptional regulation of the human LOX-1 promoter; fewer still on definitive mapping of the transcription factors involved. It is known that a wide variety of stimuli up-regulate LOX-1, usually/probably on the transcriptional level. Angiotensin II (Ang II) is one important regulator of renin-angiotensin system and stimulator LOX-1. Ang II is known to up-regulate LOX-1 transcription through an NF-kB motif located at nt −2158. Oxidized low density lipoprotein (ox-LDL) is another important cardiovascular regulator, particularly of atherosclerotic disease, and a strong stimulator of LOX-1. Ox-LDL is known to up-regulate LOX-1 transcription through an Oct-1 motif located at nt −1556. The subsequent enhanced LOX-1 receptor numbers and their binding by ox-LDL ligand triggers a positive feedback loop, increasing further LOX-1 expression, with a presently unknown regulatory governor. The Oct-1 gene also has its own Oct-1-driven positive feedback loop, which likely also contributes to LOX-1 up-regulation. There is also data which suggests the involvement of the transcription factor AP-1 during stimulation with Phorbol 12-myristate acetate. While the importance of NF-κB as a transcriptional regulator of cardiovascular-relevant genes is well known, the importance of Oct-1 is not. Data suggests that Oct-1-mediated up-regulation of transcription is an early event in the stimulation of LOX-1 by ox-LDL. Yet Oct-1 also down-regulates cardiovascular-relevant genes by suppressing NF-κB transactivation. Thus, Oct-1 is presently somewhat of an enigma, up-regulating and down-regulating genes seemingly at random without an overall theme (with the exception of cell cycle). Yet the up-regulation of LOX-1 by ox-LDL is a very important event in atherogenesis (both early and late) and Oct-1 is, therefore, an important transcriptional gatekeeper of this important atherogenic trigger.

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Authors and Affiliations

  1. Central Arkansas Veterans Healthcare System, 111J, 4300 West 7th Street, Little Rock, AR, 72205, USA

    Paul L. Hermonat, Hongqing Zhu, Maohua Cao & Jawahar L. Mehta

  2. Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, AR, 72205, USA

    Paul L. Hermonat, Hongqing Zhu, Maohua Cao & Jawahar L. Mehta

  3. John L. McClellan Memorial Veterans Hospital, 4300 West 7th Street, Research, Little Rock, AR, 72205, USA

    Paul L. Hermonat

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  1. Paul L. Hermonat
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Correspondence to Paul L. Hermonat.

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This study was funded by VA Merit Review and AHA grants to PLH.

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Hermonat, P.L., Zhu, H., Cao, M. et al. LOX-1 Transcription. Cardiovasc Drugs Ther 25, 393–400 (2011). https://doi.org/10.1007/s10557-011-6322-8

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