| Autor: |
Badi I; From the Experimental Cardio-Oncology and Cardiovascular Aging Unit (I.Ba., L.M., A.P., D.F., F.Z., A.R.)., Mancinelli L; From the Experimental Cardio-Oncology and Cardiovascular Aging Unit (I.Ba., L.M., A.P., D.F., F.Z., A.R.)., Polizzotto A; From the Experimental Cardio-Oncology and Cardiovascular Aging Unit (I.Ba., L.M., A.P., D.F., F.Z., A.R.)., Ferri D; From the Experimental Cardio-Oncology and Cardiovascular Aging Unit (I.Ba., L.M., A.P., D.F., F.Z., A.R.)., Zeni F; From the Experimental Cardio-Oncology and Cardiovascular Aging Unit (I.Ba., L.M., A.P., D.F., F.Z., A.R.)., Burba I; Vascular Biology and Regenerative Medicine Unit (I.Bu., G.M., G.P.)., Milano G; Vascular Biology and Regenerative Medicine Unit (I.Bu., G.M., G.P.).; Department of Heart and Vessels, Laboratory of Cardiovascular Research, University Hospital of Lausanne, Switzerland (G.M.)., Brambilla F; Chromatin Dynamics Unit, San Raffaele University, Milan, Italy (F.B., M.E.B.)., Saccu C; Vascular and Endovascular Surgery Unit (C.S.), Centro Cardiologico Monzino Istituto di ricovero e cura a carattere scientifico (IRCCS), Milan, Italy., Bianchi ME; Chromatin Dynamics Unit, San Raffaele University, Milan, Italy (F.B., M.E.B.)., Pompilio G; Vascular Biology and Regenerative Medicine Unit (I.Bu., G.M., G.P.)., Capogrossi MC; Department of Cardiology, Ochsner Medical Center, New Orleans, LA (M.C.C.)., Raucci A; From the Experimental Cardio-Oncology and Cardiovascular Aging Unit (I.Ba., L.M., A.P., D.F., F.Z., A.R.). |
| Abstrakt: |
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. |
