alvocidib and Aneurysm

Vascular aneurysm is an abnormal local dilatation of an artery that can lead to vessel rupture and sudden death. The only treatment involves surgical or endovascular repair or exclusion. There is currently no approved medical therapy for this condition. Recent data established a strong association between genetic variants in the 9p21 chromosomal region in humans and the presence of cardiovascular diseases, including aneurysms. However, the mechanisms linking this 9p21 DNA variant to cardiovascular risk are still unknown.. Here, we show that deletion of the orthologous 70-kb noncoding interval on mouse chromosome 4 (chr4(Δ70kb/Δ70kb) mice) is associated with reduced aortic expression of cyclin-dependent kinase inhibitor genes p19Arf and p15Inkb. Vascular smooth muscle cells from chr4(Δ70kb/Δ70kb) mice show reduced transforming growth factor-β-dependent canonical Smad2 signaling but increased cyclin-dependent kinase-dependent Smad2 phosphorylation at linker sites, a phenotype previously associated with tumor growth and consistent with the mechanistic link between reduced canonical transforming growth factor-β signaling and susceptibility to vascular diseases. We also show that targeted deletion of the 9p21 risk interval promotes susceptibility to aneurysm development and rupture when mice are subjected to a validated model of aneurysm formation. The vascular disease of chr4(Δ70kb/Δ70kb) mice is prevented by treatment with a cyclin-dependent kinase inhibitor.. The results establish a direct mechanistic link between 9p21 noncoding risk interval and susceptibility to aneurysm and may have important implications for the understanding and treatment of vascular diseases.

Topics: Aneurysm; Animals; Cells, Cultured; Chromosomes; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p19; Disease Models, Animal; Disease Susceptibility; Flavonoids; Gene Expression; Kaplan-Meier Estimate; Matrix Metalloproteinase 12; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Phenotype; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Risk Factors; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta