MicroRNA-34a promotes vascular smooth muscle cells calcification by downregulating SIRT1 and Axl
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 (VSMC) towards an osteochondrogenic lineage resulting in arterial wall mineralization. microRNA-34a (miR-34a) increases with age in aortas and induces VSMC senescence through the modulation of its target SIRT1. In this study, we aimed to investigate whether miR-34a regulates VC. We found that miR-34a and Runx2 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 and Runx2 and the senescence p16 and p21 markers. In this model, miR-34a upregulation was transient and preceded aorta mineralization. Mir34a-/- SMC were less prone to undergo senescence and under osteogenic conditions deposited less calcium compared to Mir34a+/+ cells. Furthermore, unlike in Mir34a+/+ SMC, the known VC inhibitors SIRT1 and Axl were only partially downregulated in calcifying Mir34a-/- SMC. Strikingly, constitutive miR-34a overexpression to senescence-like levels in human aortic smooth muscle cells (HASMC) increased calcium deposition and enhanced Axl and SIRT1 decrease during calcification. Notably, we also showed that miR-34a directly decreased Axl expression in HASMC and restoration of its levels partially rescued miR-34a-dependent growth arrest. MiR-34a promotes VC via VSMC 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.