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Arterial calcifications and increased expression of vitamin D receptor targets in mice lacking TIF1alpha.

ABSTRACT: Calcification of arteries is a major risk factor for cardiovascular mortality in humans. Using genetic approaches, we demonstrate here that the transcriptional intermediary factor 1alpha (TIF1alpha), recently shown to function as a tumor suppressor in murine hepatocytes, also participates in a molecular cascade that prevents calcifications in arterioles and medium-sized arteries. We further provide genetic evidence that this function of TIF1alpha is not exerted in hepatocytes. The sites of ectopic calcifications in mutant mice lacking TIF1alpha resemble those seen in mice carrying an activating mutation of the calcium sensor receptor (Casr) gene and, in TIF1alpha-deficient kidneys, Casr expression is increased together with that of many other vitamin D receptor (VDR) direct target genes, namely Car2, Cyp24a1, Trpv5, Trpv6, Calb1, S100g, Pthlh, and Spp1. Thus, our data indicate that TIF1alpha represses the VDR pathway in kidney and suggest that an up-regulation of Casr expression in this organ could account for ectopic calcifications generated upon TIF1alpha deficiency. Interestingly, the calcifying arteriopathy of TIF1alpha-null mutant mice shares features with the human age-related Mönckeberg's disease and, overall, the TIF1alpha-null mutant pathological phenotype supports the hypothesis that aging is promoted by increased activity of the vitamin D signaling pathway.

SUBMITTER: Ignat M

PROVIDER: S-EPMC2268182 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Arterial calcifications and increased expression of vitamin D receptor targets in mice lacking TIF1alpha.

Ignat Mihaela M Teletin Marius M Tisserand Johan J Khetchoumian Konstantin K Dennefeld Christine C Chambon Pierre P Losson Régine R Mark Manuel M

Proceedings of the National Academy of Sciences of the United States of America 20080219 7

Calcification of arteries is a major risk factor for cardiovascular mortality in humans. Using genetic approaches, we demonstrate here that the transcriptional intermediary factor 1alpha (TIF1alpha), recently shown to function as a tumor suppressor in murine hepatocytes, also participates in a molecular cascade that prevents calcifications in arterioles and medium-sized arteries. We further provide genetic evidence that this function of TIF1alpha is not exerted in hepatocytes. The sites of ectop ...[more]

PMID: 18287084

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Project description:BackgroundArterial calcifications are associated with increased cardiovascular risk, but the genetic basis of this association is unclear.MethodsWe performed clinical, radiographic, and genetic studies in three families with symptomatic arterial calcifications. Single-nucleotide-polymorphism analysis, targeted gene sequencing, quantitative polymerase-chain-reaction assays, Western blotting, enzyme measurements, transduction rescue experiments, and in vitro calcification assays were performed.ResultsWe identified nine persons with calcifications of the lower-extremity arteries and hand and foot joint capsules: all five siblings in one family, three siblings in another, and one patient in a third family. Serum calcium, phosphate, and vitamin D levels were normal. Affected members of Family 1 shared a single 22.4-Mb region of homozygosity on chromosome 6 and had a homozygous nonsense mutation (c.662C→A, p.S221X) in NT5E, encoding CD73, which converts AMP to adenosine. Affected members of Family 2 had a homozygous missense mutation (c.1073G→A, p.C358Y) in NT5E. The proband of Family 3 was a compound heterozygote for c.662C→A and c.1609dupA (p.V537fsX7). All mutations found in the three families result in nonfunctional CD73. Cultured fibroblasts from affected members of Family 1 showed markedly reduced expression of NT5E messenger RNA, CD73 protein, and enzyme activity, as well as increased alkaline phosphatase levels and accumulated calcium phosphate crystals. Genetic rescue experiments normalized the CD73 and alkaline phosphatase activity in patients' cells, and adenosine treatment reduced the levels of alkaline phosphatase and calcification.ConclusionsWe identified mutations in NT5E in members of three families with symptomatic arterial and joint calcifications. This gene encodes CD73, which converts AMP to adenosine, supporting a role for this metabolic pathway in inhibiting ectopic tissue calcification. (Funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute of the National Institutes of Health.).

Project description:BackgroundIn clinical practice, calcifications seen on computed tomographic studies within the large brain arteries are often referred to as a surrogate marker for cholesterol-mediated atherosclerosis. However, limited data exist to support the association between calcification and atherosclerosis. In this study, we examined if intracranial arterial calcifications were associated with cholesterol-mediated intracranial large artery atherosclerosis (ILAA) within the arteries of the circle of Willis in an autopsy-based sample.MethodsWe carried out a cross-sectional analysis of histopathological characteristics of brain large arteries obtained from autopsy cases. Brain large arteries were examined for evidences of calcifications, which were rated as macroscopic (coalescent) and microscopic (scattered). In addition to calcification, we also obtained measurement of the arterial wall and the presence of ILAA and nonatherosclerotic arterial fibrosis. We built hierarchical models adjusted for demographic and vascular risk factors to assess the relationship between calcification and ILAA.ResultsIn univariate analysis, the presence of any arterial calcifications was associated with cerebral infarcts (29% vs. 14%, P<.01). Multivariate analysis revealed that among all calcifications, coalescent calcifications were not associated with ILAA. In contrast, scattered calcifications were associated with ILAA (P<.001), decreased lumen diameter (-1.87 +/- 0.41 mm, P≤.001), and increased luminal stenosis (0.03% +/- 0.01%, P≤.006). These findings were independent of age, sex, or other vascular risk factors.ConclusionsThis study demonstrates that coalescent calcifications in brain large arteries, although associated with morbidity, are not synonymous with cholesterol-driven ILAA. Understanding the precise pathological components of cerebrovascular disease, including nonatherosclerotic arterial calcifications, will help develop individualized therapies beyond amelioration of traditional risk factors such as hyperlipidemia.

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Arterial calcifications and increased expression of vitamin D receptor targets in mice lacking TIF1alpha.

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Arterial calcifications and increased expression of vitamin D receptor targets in mice lacking TIF1alpha.

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