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Enhanced Megakaryopoiesis and Platelet Activity in Hypercholesterolemic, B6-Ldlr-/-, Cdkn2a-Deficient Mice.

ABSTRACT: Genome-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.Platelet 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.Together, 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.

SUBMITTER: Wang W

PROVIDER: S-EPMC4917436 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Enhanced Megakaryopoiesis and Platelet Activity in Hypercholesterolemic, B6-Ldlr-/-, Cdkn2a-Deficient Mice.

Wang Wei W Oh Seon S Koester Mark M Abramowicz Sandra S Wang Nan N Tall Alan R AR Welch Carrie L CL

Circulation. Cardiovascular genetics 20160420 3

<h4>Background</h4>Genome-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, ...[more]

PMID: 27098250

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Project description:Hypercholesterolemia resulting in atherosclerosis is associated with an increased risk of ischemic heart disease and colorectal cancer (CRC). However, the roles of apoliprotein (Apo) E (Apoe) and low-density lipoprotein (Ldl) receptor (Ldlr) in colorectal carcinogenesis have not yet been investigated. In this study, we examined the susceptibility of Apoe-deficient and Ldlr-deficient mice, which are genetic animal models of atherosclerosis to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal carcinogenesis. In Experiment 1, male Apoe-deficient (n = 20) and wild type (WT) mice (C57BL/6J, n = 21) were treated with a single intraperitoneal (i.p.) injection of AOM (10 mg/kg body weight) and then given 1.5% DSS in drinking water for seven days. They were maintained up to week 20 and sacrificed for the histopathological examination of colorectal tumors. The mRNA expression of cyclooxygenase (Cox)-2, inducible nitric oxide synthase (Nos2), tumor necrosis factor (Tnf)-? interleukin (Il)-1?, and Il-6 was assayed in the colorectal mucosa. In Experiment 2, male Ldlr-deficient (n = 14) and WT mice (C57BL/6J, n = 10) were given a single i.p. injection of AOM (10 mg/kg body weight) and then given 2% DSS in drinking water for seven days. They were sacrificed at week 20 to evaluate their colorectum histopathologically. In Experiment 1, the multiplicity of CRCs was significantly higher in the Apoe-deficient mice (2.75 ± 1.48) than in the WT mice (0.62 ± 0.67). The serum lipoprotein levels in the Apoe-deficient mice were also significantly higher than in the WT mice. In Experiment 2, the incidence (29%) and multiplicity (0.50 ± 0.94) of CRCs in the Ldlr mice were significantly lower than in the WT mice (80% incidence and 3.10 ± 2.38 multiplicity). The mRNA expression of two inducible enzymes and certain pro-inflammatory cytokines in the colorectum of each genotype was greater than in the respective WT mice. The values in the Apoe-deficient mice were much greater than in the Ldlr mice. These findings suggest that Apoe-deficient mice showed increased susceptibility to inflammation-associated colorectal carcinogenesis due to their high reactivity to inflammatory stimuli.

Dataset Information

Enhanced Megakaryopoiesis and Platelet Activity in Hypercholesterolemic, B6-Ldlr-/-, Cdkn2a-Deficient Mice.

Publications

Enhanced Megakaryopoiesis and Platelet Activity in Hypercholesterolemic, B6-Ldlr-/-, Cdkn2a-Deficient Mice.

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