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  Deficiency of the Stroke Relevant HDAC9 Gene Attenuates Atherosclerosis in Accord With Allele-Specific Effects at 7p21.1

Azghandi, S., Prell, C., van der Laan, S. W., Schneider, M., Malik, R., Berer, K., et al. (2015). Deficiency of the Stroke Relevant HDAC9 Gene Attenuates Atherosclerosis in Accord With Allele-Specific Effects at 7p21.1. STROKE, 46(1), 197-202. doi:10.1161/STROKEAHA.114.007213.

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Azghandi, Sepiede1, Autor
Prell, Caroline1, Autor
van der Laan, Sander W.1, Autor
Schneider, Manuela1, Autor
Malik, Rainer1, Autor
Berer, Kerstin2, Autor           
Gerdes, Norbert1, Autor
Pasterkamp, Gerard1, Autor
Weber, Christian1, Autor
Haffner, Christof1, Autor
Dichgans, Martin1, Autor
Affiliations:
1external, ou_persistent22              
2Emeritus Group: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society, ou_1113547              

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Schlagwörter: REGULATORY T-CELLS; ISCHEMIC-STROKE; HISTONE DEACETYLASES; PROMOTES; ASSOCIATION; INHIBITION; EXPRESSION; DISEASE; DEATH; RISKatherosclerosis; HDAC9 protein, human; stroke;
 Zusammenfassung: Background and Purpose-Recent genome-wide association studies identified the histone deacetylase 9 (HDAC9) gene region as a major risk locus for large-vessel stroke and coronary artery disease. However, the mechanisms linking variants at this locus to vascular risk are poorly understood. In this study, we investigated the candidacy and directionality of HDAC9 in atherosclerosis and analyzed associations between risk alleles at 7p21.1 and plaque characteristics. Methods-Allele-dependent expression of HDAC9 was analyzed in human peripheral blood mononuclear cells of healthy donors. Effects of HDAC9 deficiency on atherosclerotic plaques were investigated in 18- and 28-week-old ApoE(-/-) mice by histology and immunohistochemistry. We further performed detailed plaque phenotyping and genotyping of rs2107595, the lead single-nucleotide polymorphism for large-vessel stroke, in carotid endarterectomy samples of 1858 subjects from the Athero-Express study. Results-Gene expression studies in peripheral blood mononuclear cells revealed increased mRNA levels of HDAC9 but not of neighboring genes (TWIST1/FERD3L) in risk allele carriers of rs2107595. Compared with HDAC9(+/+) ApoE(-/-) mice, HDAC9(-/-)ApoE(-/-) mice exhibited markedly reduced lesion sizes throughout atherosclerotic aortas and significantly less advanced lesions. The proportion of Mac3-positive macrophages was higher in plaques from HDAC9(-/-)ApoE(-/-) mice, but this was largely because of a lower proportion of advanced lesions. Analysis of human atherosclerotic plaques revealed no association between rs2107595 and specific plaque characteristics. Conclusions-Our results suggest that HDAC9 represents the disease-relevant gene at the stroke and coronary artery disease risk locus on 7p21.1, and that risk alleles in this region mediate their effects through increased HDAC9 expression. Targeted inhibition of HDAC9 might be a viable strategy to prevent atherosclerosis.

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Sprache(n): eng - English
 Datum: 2015-01
 Publikationsstatus: Erschienen
 Seiten: 13
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: ISI: 000346735800046
DOI: 10.1161/STROKEAHA.114.007213
 Art des Abschluß: -

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Titel: STROKE
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA : LIPPINCOTT WILLIAMS & WILKINS
Seiten: - Band / Heft: 46 (1) Artikelnummer: - Start- / Endseite: 197 - 202 Identifikator: ISSN: 0039-2499