9.2 DELETION OF CHROMOSOME 9P21 NONCODING CARDIOVASCULAR RISK INTERVAL IN MICE INDUCES A PROTHROMBOTIC PHENOTYPE
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- Abstract
Background: SNPs on chromosome 9p21.3 risk locus have been associated with cardiovascular diseases. We have established a direct mechanistic link between 9p21 noncoding risk interval and susceptibility to aneurysm in a mouse model with a targeted deletion of the 9p21 noncoding cardiovascular disease risk interval.
The deficiency of transcripts encoded by this locus predisposes to a pro-thrombotic phenotype and arterial stiffening in this mouse model and in humans with 9p21 DNA variants.
Methods: Carotid blood flow following FeCl3 application was monitored via Doppler profiles. Results: The deletion of the orthologous 70-kb noncoding interval on mouse chromosome 4 (chr4Δ70kb/Δ70kb), synthetic to human chromosome 9p21, predisposes to arterial thrombosis. The time to occlusion in a FeCl3-induced carotid thrombosis model was significantly decreased by 30% in the absence of the locus and confirmed by a new model of physiological thrombosis. There was no difference between groups in blood pressure, carotid stiffness parameters (diameter and distensibility for a given level of arterial pressure) or in vascular structure. We explored the potential impact of the deletion locus on thrombin generation as well as on platelet aggregation and reactivity all were increased compared to controls. In 100 healthy carriers of the 9p21 risk T allele display an increased aortic arterial stiffness compared with carriers of the C allele.
Conclusion: These results establish a direct link between variants or deletion in the 9p21 non-coding risk interval and increased platelet reactivity and thrombin generation predisposing to thrombosis in mouse and increased arterial stiffness in aged population.
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TY - JOUR AU - Amel Mohamadi AU - Mustapha Bourhim AU - Gemma Basatemur AU - Huguette Louis AU - Athanase Benetos AU - Patrick Lacolley AU - Ziad Mallat AU - Veronique Regnault PY - 2016 DA - 2016/11/24 TI - 9.2 DELETION OF CHROMOSOME 9P21 NONCODING CARDIOVASCULAR RISK INTERVAL IN MICE INDUCES A PROTHROMBOTIC PHENOTYPE JO - Artery Research SP - 68 EP - 68 VL - 16 IS - C SN - 1876-4401 UR - https://doi.org/10.1016/j.artres.2016.10.069 DO - 10.1016/j.artres.2016.10.069 ID - Mohamadi2016 ER -