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Published on: May 31, 2016
Arterial calcifications and increased expression of vitamin D receptor targets in mice lacking TIF1alpha
Mihaela Ignat1, Marius Teletin, Johan Tisserand
1Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, BP 10142, 67404 Illkirch Cedex, France.
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.
Insights
Transcriptional intermediary factor 1alpha (TIF1alpha) prevents arterial calcification by repressing the vitamin D receptor pathway in the kidney. Loss of TIF1alpha leads to ectopic calcifications, suggesting a role in aging and cardiovascular disease.
Area of Science:
- Vascular Biology
- Molecular Genetics
- Renal Physiology
Background:
- Arterial calcification is a significant risk factor for cardiovascular mortality.
- Transcriptional intermediary factor 1alpha (TIF1alpha) is known to function as a tumor suppressor in hepatocytes.
- The role of TIF1alpha in vascular calcification has not been previously established.
Purpose of the Study:
- To investigate the role of TIF1alpha in preventing arterial calcification.
- To determine the molecular mechanisms by which TIF1alpha regulates calcification.
- To explore the connection between TIF1alpha deficiency, vitamin D signaling, and ectopic calcification.
Main Methods:
- Genetic manipulation in mice to create TIF1alpha-deficient models.
- Analysis of calcification sites in arterioles and medium-sized arteries.
- Gene expression analysis of calcium-sensing receptor (Casr) and vitamin D receptor (VDR) target genes in kidney tissue.
Main Results:
- TIF1alpha deficiency leads to ectopic calcifications in arteries, independent of its function in hepatocytes.
- TIF1alpha-null mice exhibit increased expression of Casr and other VDR target genes in the kidney.
- The observed calcifying arteriopathy shares features with human Mönckeberg's disease.
Conclusions:
- TIF1alpha acts as a repressor of the VDR pathway in the kidney, preventing ectopic calcifications.
- Increased Casr expression in TIF1alpha-deficient kidneys likely contributes to arterial calcification.
- TIF1alpha deficiency exacerbates VDR signaling, potentially promoting aging and cardiovascular pathology.
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