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Differential Regulation of Functional Gene Clusters in Overt Coronary Artery Disease in a Transgenic Atherosclerosis-hypertensive Rat Rodel

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Abstract

Background

Human acute coronary syndrome refers to the spectrum of clinical manifestations of overt coronary artery (CAD) disease characterized by atherosclerotic plaque destabilization and resultant myocardial injury. Typically studied as distinct pathologies, emerging pathogenic paradigms implicate multiple processes beyond thrombosis and ischemic cell injury respectively, with significant pathway overlap involving inflammation, apoptosis, matrix degradation, and oxidative stress. However, all these pathways have also been implicated in still-quiescent coronary plaque progression, thus making it harder to pinpoint the turnkey events leading to overt-CAD. Analysis of transcription profiles could identify a working framework of pathogenesis distinguishing overt-CAD.

Materials and Methods

We investigated the transcription profile associated with overt-coronary artery disease (CAD), in contrast to quiescent-CAD and attenuated, quiescent-CAD using the Tg53 transgenic atherosclerosis-hypertensive rat model, which exhibits end-stage coronary heart disease simulating human acute coronary syndromes. Using a rat-specific known-gene oligonucleotide array, twice corroborated transcription profiles from four individual Tg53 rats exhibiting overt-CAD were analyzed and contrasted to transcription profiles of age-matched Tg53 rats with quiescent-CAD (pooled n = 4) and attenuated, quiescent-CAD (pooled n = 4).

Results

Tg53 male rats with overt-CAD exhibited distinct transcription profiles compared with both quiescent-CAD control groups. Functional gene cluster analysis detects upregulation of genes involved in inflammation (interleukin-1, interleukin-18, FcγII receptor, thyrotropin releasing hormone), matrix balance (membrane type metalloproteinase, TIMP-1, lysyl oxidase), oxidized LDL entry (endothelial oxLDL receptor), which contrast deinduced gene clusters involved in angiogenesis, proliferation, metabolism, ion transport and adrenergic receptors.

Conclusions

The data demonstrate that transcriptionally mediated events distinguish the onset of overt-CAD and identify a first list of putative “turnkey” genes. This altered molecular framework implies an altered “hardwiring” which a priori would require multifaceted, targeted intervention-currently not implemented to date. Although more studies are necessary, early concordance with current pathogenic paradigms of human coronary plaque destabilization and post-ischemic myocardial response provides translational significance to observations and hypotheses.

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Acknowledgments

We acknowledge excellent technical assistance of Kimberly Zander and Sarah T. Cruz. This work was supported in part by a grant from the NIH National Heart, Lung, and Blood Institute (HL 62857) and by a grant-in-aid from the American Heart Association.

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Authors and Affiliations

  1. Unit of Molecular Genetics, Whitaker Cardiovascular Institute-W609, Section of Molecular Medicine, Evans, Department of Medicine, Boston University School of Medicine, 700 Albany Street, Boston, MA, 02118, USA

    Victoria L. M. Herrera, Tamara Didishvili, Lyle V. Lopez & Nelson Ruiz-Opazo

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  1. Victoria L. M. Herrera
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  2. Tamara Didishvili
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  3. Lyle V. Lopez
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  4. Nelson Ruiz-Opazo
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Correspondence to Victoria L. M. Herrera.

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Herrera, V.L.M., Didishvili, T., Lopez, L.V. et al. Differential Regulation of Functional Gene Clusters in Overt Coronary Artery Disease in a Transgenic Atherosclerosis-hypertensive Rat Rodel. Mol Med 8, 367–375 (2002). https://doi.org/10.1007/BF03402017

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  • DOI: https://doi.org/10.1007/BF03402017

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