miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase)
| العنوان: | miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase) |
|---|---|
| المؤلفون: | Marco Bianchi, Francesca Brambilla, Angela Raucci, Ileana Badi, Claudio Saccu, Andrea Polizzotto, Giulio Pompilio, Debora Ferri, Giuseppina Milano, Maurizio C. Capogrossi, Ilaria Burba, Luigi Mancinelli, Filippo Zeni |
| المساهمون: | Badi, Ileana, Mancinelli, Luigi, Polizzotto, Andrea, Ferri, Debora, Zeni, Filippo, Burba, Ilaria, Milano, Giuseppina, Brambilla, Francesca, Saccu, Claudio, Bianchi, Marco E, Pompilio, Giulio, Capogrossi, Maurizio C, Raucci, Angela |
| المصدر: | Arteriosclerosis, thrombosis, and vascular biology, vol. 38, no. 9, pp. 2079-2090 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Aging, Vascular smooth muscle, Core Binding Factor Alpha 1 Subunit, 030204 cardiovascular system & hematology, Muscle, Smooth, Vascular, Mice, 0302 clinical medicine, Sirtuin 1, animal, Aorta, Cells, Cultured, Cellular Senescence, Mice, Knockout, biology, Chemistry, Transdifferentiation, SOX9 Transcription Factor, Up-Regulation, Cell biology, vascular calcification, Cardiology and Cardiovascular Medicine, Adult, Senescence, mice, Myocytes, Smooth Muscle, Down-Regulation, Young Adult, 03 medical and health sciences, Downregulation and upregulation, Proto-Oncogene Proteins, medicine, Animals, Humans, human, Vascular Calcification, Aging/pathology, Aorta/metabolism, Cell Proliferation, Cellular Senescence/physiology, Core Binding Factor Alpha 1 Subunit/metabolism, MicroRNAs/metabolism, Muscle, Smooth, Vascular/cytology, Muscle, Smooth, Vascular/metabolism, Myocytes, Smooth Muscle/metabolism, Proto-Oncogene Proteins/metabolism, Receptor Protein-Tyrosine Kinases/metabolism, SOX9 Transcription Factor/metabolism, Sirtuin 1/metabolism, aging, humans, senescence, AXL receptor tyrosine kinase, Cell growth, Receptor Protein-Tyrosine Kinases, medicine.disease, Axl Receptor Tyrosine Kinase, MicroRNAs, 030104 developmental biology, biology.protein, Calcification |
| الوصف: | Objective— Vascular calcification (VC) is age dependent and a risk factor for cardiovascular and all-cause mortality. VC involves the senescence-induced transdifferentiation of vascular smooth muscle cells (SMCs) toward an osteochondrogenic lineage resulting in arterial wall mineralization. miR-34a increases with age in aortas and induces vascular SMC senescence through the modulation of its target SIRT1 (sirtuin 1). In this study, we aimed to investigate whether miR-34a regulates VC. Approach and Results— We found that miR-34a and Runx2 (Runt-related transcription factor 2) expression correlates in young and old mice. Mir34a +/+ and Mir34a −/− mice were treated with vitamin D, and calcium quantification revealed that Mir34a deficiency reduces soft tissue and aorta medial calcification and the upregulation of the VC Sox9 (SRY [sex-determining region Y]-box 9) and Runx2 and the senescence p16 and p21 markers. In this model, miR-34a upregulation was transient and preceded aorta mineralization. Mir34a −/− SMCs were less prone to undergo senescence and under osteogenic conditions deposited less calcium compared with Mir34a +/+ cells. Furthermore, unlike in Mir34a +/+ SMC, the known VC inhibitors SIRT1 and Axl (AXL receptor tyrosine kinase) were only partially downregulated in calcifying Mir34a −/− SMC. Strikingly, constitutive miR-34a overexpression to senescence-like levels in human aortic SMCs increased calcium deposition and enhanced Axl and SIRT1 decrease during calcification. Notably, we also showed that miR-34a directly decreased Axl expression in human aortic SMC, and restoration of its levels partially rescued miR-34a-dependent growth arrest. Conclusions— miR-34a promotes VC via vascular SMC mineralization by inhibiting cell proliferation and inducing senescence through direct Axl and SIRT1 downregulation, respectively. This miRNA could be a good therapeutic target for the treatment of VC. |
| وصف الملف: | application/pdf |
| تدمد: | 1524-4636 1079-5642 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::199530fe14e86bc3c493ce4b85c3110cTest https://doi.org/10.1161/atvbaha.118.311298Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....199530fe14e86bc3c493ce4b85c3110c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244636 10795642 |
|---|