Abcc6 and coronary artery calcification

Coronary artery calcification is one of the determinant cardiovascular risk factor for CAD/MI, which leads to increased morbidity and mortality in western countries. Our group have reported the heritability of CAC and worked intensively on genetic predisposition of certain laboratory inbred strains to calcification. These mice were used later on to understand the underlying pathological processes. Based on quantitative trait locus (QTL) analysis, fine mapping and ultrafine mapping strategies Abcc6 was finally identified as causal gene for dystrophic cardiac calcification in mice within the Dyscalc1 major locus on mouse chromosome 7. Interestingly, mutations in ABCC6 were also identified from other research groups to cause calcification in two human rare disorders pseudoxanthoma elasticum (PXE) and general arterial calcification of infancy (GACI).
Abcc6 encodes for an Abc-transporter, which is expressed mainly in liver. We and other PXE/GACI scientific researchers work together at international level to understand the underlying pathological mechanisms and identify the substrate (s) transported by this membrane transporter. Very recently our group demonstrated that dystrophic calcification shares many features with osteogenic processes and identified Runx2 as determinant osteogenic transcription factor enhancing calcification in mice deficient for Abcc6 via increased transcription of its downstream gene osteopontin. Furthermore and using gene transfer approach our group worked together with the research group of Prof. Le Saux in Hawaii as well as the research group of Prof. Varadi in Budapest, Hungary to demonstrate for the first time that a low hepatic level of the functional Abcc6 rescue calcification in mice.

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