Abstract: SA-PO861
Maintenance of Vascular Microrna-145 Levels Effectively Attenuates Uremia- and High Phosphate-Induced Aortic Calcification
Session Information
- Vascular Calcification
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Mineral Disease
- 1205 Vascular Calcification
Authors
- Panizo, Sara, Hospital Universitario Central de Asturias, Instituto Reina Sofía de Investigación, REDinREN del ISCIII, Oviedo, Spain
- Carrillo-Lopez, Natalia, Hospital Universitario Central de Asturias, Instituto Reina Sofía de Investigación, REDinREN del ISCIII, Oviedo, Spain
- Arcidiacono, M. Vittoria, University of Ferrara, Ferrara, Italy
- De la fuente, Sandra, IRB Lleida, Lleida, Spain
- Castro, Anabel, IRB Lleida, Lleida, Spain
- Naves, Manuel, Hospital Universitario Central de Asturias, Instituto Reina Sofía de Investigación, REDinREN del ISCIII, Oviedo, Spain
- Rodriguez, Isabel, Hospital Universitario Central de Asturias, Instituto Reina Sofía de Investigación, REDinREN del ISCIII, Oviedo, Spain
- Cannata-Andia, Jorge B., Hospital Universitario Central de Asturias, Instituto Reina Sofía de Investigación, REDinREN del ISCIII, Oviedo, Spain
- Dusso, Adriana S., Hospital Universitario Central de Asturias, Instituto Reina Sofía de Investigación, REDinREN del ISCIII, Oviedo, Spain
Background
In CKD, the control of vascular calcification (VC) is essential to reduce the risk of cardiovascular mortality. Herein, maintenance of mature microRNA-145 (miR-145) was examined as an anti-calcifying strategy because: a) miR-145 is the prevalent miR in vascular smooth muscle cells (VSMC) and essential to maintain their contractile phenotype; b) miR-145 targets osteogenic Osterix in osteoblasts; c) high phosphate (P) reduces normal VSMC miR-145 levels supporting a link between high P, miR-145 reductions, increased Osterix and VC.
Methods
Aortic calcium (Ca), pri-miR-145, miR-145 content and mRNA levels of vascular/osteogenic markers (a-actin and Osterix) were measured in: a) A7r5 cells (rat aorta VSMC), with or without miR-145 over-expression or silencing, and exposed to calcifying (2mM Ca; 3mM P) or non calcifying (1mM Ca; 1mM P) conditions for 4 days; b) Aortas from either 5/6 nephrectomized (NX) rats fed high dietary P for a month or from 3/4NX mice fed normal dietary P for 3½ months.
Results
In A7r5 cells, the exposure to calcifying media (CM) significantly reduced miR-145 levels in part through a 30% downregulation of pri-miR-145 (p<0.04) which supports the inhibition of miR-145 gene expression. Also, while miR-145 silencing further exacerbated the osteogenic differentiation (reduced α-actin and increased Osterix mRNAs) and Ca deposition induced by the CM, miR-145 overexpression markedly attenuated both. Importantly, miR-145 silencing also reduced α-actin and increased Osterix under non-CM. Accordingly, in 5/6NX rats fed high P, an inflexion point value was found for aortic miR-145 that accurately discriminated aortas with higher than normal Ca content (miR-145 levels below the threshold) from those with normal Ca content (aortic miR-145 above the threshold) (p<0.005, n=24). Also, in the mouse model mimicking slow human CKD progression with no hyperphosphatemia, an 85% reduction of aortic miR-145 concurred with an 80% reduction in aortic α-actin but no significant increases in Osterix or Ca content.
Conclusion
Maintaining vascular miR-145 levels should attenuate the vascular phenotype switch prompting osteogenic differentiation and calcification from early CKD stages and regardless of serum P.
Funding
- Government Support - Non-U.S.