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Physiol Genomics. 2014 Jun 15;46(12):418-28. doi: 10.1152/physiolgenomics.00004.2014. Epub 2014 May 1.

Protease inhibitor 15, a candidate gene for abdominal aortic internal elastic lamina ruptures in the rat.

Author information

1
Max Delbrück Center for Molecular Medicine, Berlin, Germany;
2
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom;
3
Institute of Cardiometabolism and Nutrition, University Pierre & Marie Curie, Hospital Pitié Salpetrière, Paris, France; and.
4
Max Delbrück Center for Molecular Medicine, Berlin, Germany; nhuebner@mdc-berlin.de.
5
Inserm U698-University Paris 7, Hôpital Bichat, Paris, France.

Abstract

The inbred Brown Norway (BN) rat develops spontaneous ruptures of the internal elastic lamina (RIEL) of the abdominal aorta (AA) and iliac arteries. Prior studies with crosses of the BN/Orl RJ (susceptible) and LOU/M (resistant) showed the presence of a significant QTL on chromosome 5 and the production of congenic rats proved the involvement of this locus. In this study, we further dissected the above-mentioned QTL by creating a new panel of LOU.BN(chr5) congenic and subcongenic lines and reduced the locus to 5.2 Mb. Then we studied 1,002 heterogeneous stock (HS) rats, whose phenotyping revealed a low prevalence and high variability for RIEL. High-resolution mapping in the HS panel detected the major locus on chromosome 5 (log P > 35) and refined it to 1.4 Mb. Subsequently, RNA-seq analysis on AA of BN, congenics, and LOU revealed expression differences for only protease inhibitor 15 (Pi15) gene and a putative long intergenic noncoding RNA (lincRNA) within the linkage region. The high abundance of lincRNA with respect to reduced Pi15 expression, in conjunction with exertion of longitudinal strain, may be related to RIEL, indicating the potential importance of proteases in biological processes related to defective aortic internal elastic lamina structure. Similar mechanisms may be involved in aneurysm initiation in the human AA.

KEYWORDS:

heterogeneous stock; protease inhibitor 15; rupture of the internal elastic lamina; subcongenics

[Indexed for MEDLINE]
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