Published Online
on October 19, 2009

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Original Article

Disruption of the Aortic Elastic Lamina and Medial Calcification Share Genetic Determinants in Mice

Susanna S. Wang¹; Lisa J. Martin^1,3; Eric E. Schadt²; Haijin Meng¹; Xuping Wang¹; Wei Zhao¹; Leslie Ingram–Drake¹; Martina Nebohacova¹; Margarete Mehrabian¹; Thomas A. Drake¹ and Aldons J. Lusis¹

¹ UCLA David Geffen School of Medicine, Los Angeles, CA;
² Pacific Biosciences, Menlo Park, CA

^* Corresponding author; email: fulcrum{at}ucla.edu

Background—Disruption of the elastic lamina, as an early indicator of aneurysm formation, and vascular calcification frequently occur together in atherosclerotic lesions of humans.

Methods and Results—We now report evidence of shared genetic basis for disruption of the elastic lamina (medial disruption) and medial calcification in an F₂ mouse intercross between C57BL/6J and C3H/HeJ on a hyperlipidemic apolipoprotein E (ApoE-/-) null background. We identified three quantitative trait loci (QTLs), on chromosomes 6, 13 and 18, that are common to both traits, and two additional QTLs for medial calcification on chromosomes 3 and 7. Medial disruption, including severe disruptions leading to aneurysm formation, and medial calcification were highly correlated and occurred concomitantly in the cross. The chromosome 18 locus showed a striking male sex-specificity for both traits. To identify candidate genes, we integrated data from microarray analysis, genetic segregation, and clinical traits. The chromosome 7 locus contains the Abcc6 gene, known to mediate myocardial calcification. Using transgenic complementation, we show that Abcc6 also contributes to aortic medial calcification.

Conclusions—Our data indicate that calcification, though possibly contributory, does not always lead to medial disruption, and that in addition to aneurysm formation, medial disruption may be the precursor to calcification.

Key Words: aneurysm • cardiovascular diseases • heart diseases • mapping • Abcc6 • Alox5 • elastic lamina disruption • medial calcification • vascular calcification