ArticleCirculation. Cardiovascular genetics2016
Enhanced Megakaryopoiesis and Platelet Activity in Hypercholesterolemic, B6-Ldlr-/-, Cdkn2a-Deficient Mice.
Article in Circulation. Cardiovascular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 20 citations in OpenAlex.
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- Deciphering the Role of Copper Homeostasis in Atherosclerosis: From Molecular Mechanisms to Therapeutic Targets.International journal of molecular sciences · 2024Review
- Oxidised Low-Density Lipoprotein-Induced Platelet Hyperactivity-Receptors and Signalling Mechanisms.International journal of molecular sciences · 2022Review
- Ferroptosis and Autophagy-Related Genes in the Pathogenesis of Ischemic Cardiomyopathy.Frontiers in cardiovascular medicine · 2022Article
- Inhibition of JAK2 Suppresses Myelopoiesis and Atherosclerosis in ApoeCardiovascular drugs and therapy · 2020Article
- Type 1 diabetic mellitus patients with increased atherosclerosis risk display decreased CDKN2A/2B/2BAS gene expression in leukocytes.Journal of translational medicine · 2019Article
- LncRNA ANRIL Expression and ANRIL Gene Polymorphisms Contribute to the Risk of Ischemic Stroke in the Chinese Han Population.Cellular and molecular neurobiology · 2018Article
- DNA Methylation Pattern and mRNA Expression Level of E-Cadherin and P16 Genes in Thrombotic Disorders.Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/HemostasisArticle
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7 authors at 1 institution in 1 country.
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Abstract
backgroundGenome-wide association studies for coronary artery disease/myocardial infarction revealed a 58 kb risk locus on 9p21.3. Refined genetic analyses revealed unique haplotype blocks conferring susceptibility to atherosclerosis per se versus risk for acute complications in the presence of underlying coronary artery disease. The cell proliferation inhibitor locus, CDKN2A, maps just upstream of the myocardial infarction risk block, is at least partly regulated by the noncoding RNA, ANRIL, overlapping the risk block, and has been associated with platelet counts in humans. Thus, we tested the hypothesis that CDKN2A deficiency predisposes to increased platelet production, leading to increased platelet activation in the setting of hypercholesterolemia. METHODS AND
resultsPlatelet production and activation were measured in B6-Ldlr(-/-)Cdkn2a(+/-) mice and a congenic strain carrying the region of homology with the human 9p21.3/CDKN2A locus. The strains exhibit decreased expression of CDKN2A (both p16(INK4a) and p19(ARF)) but not CDKN2B (p15(INK4b)). Compared with B6-Ldlr(-/-) controls, both Cdkn2a-deficient strains exhibited increased platelet counts and bone marrow megakaryopoiesis. The platelet overproduction phenotype was reversed by treatment with cyclin-dependent kinase 4/6 inhibitor, PD0332991/palbociclib, that mimics the endogenous effect of p16(INK4a). Western diet feeding resulted in increased platelet activation, increased thrombin/antithrombin complex, and decreased bleeding times in Cdkn2a-deficient mice compared with controls.
conclusionsTogether, the data suggest that one or more Cdkn2a transcripts modulate platelet production and activity in the setting of hypercholesterolemia, amenable to pharmaceutical intervention. Enhanced platelet production and activation may predispose to arterial thrombosis, suggesting an explanation, at least in part, for the association of 9p21.3 and myocardial infarction.
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