Year-end Sale % OFF 
Abstract
Vascular calcification (VC) is regarded as an important pathological change lacking effective treatment and associated with high mortality. Sirtuin 6 (SIRT6) is a member of the Sirtuin family, a class III histone deacetylase and a key epigenetic regulator. SIRT6 has a protective role in patients with chronic kidney disease (CKD). However, the exact role and molecular mechanism of SIRT6 in VC in patients with CKD remain unclear. Here, we demonstrated that SIRT6 was markedly downregulated in peripheral blood mononuclear cells (PBMCs) and in the radial artery tissue of patients with CKD with VC. SIRT6-transgenic (SIRT6-Tg) mice showed alleviated VC, while vascular smooth muscle cell–specific (VSMC-specific) SIRT6 knocked-down mice showed severe VC in CKD. SIRT6 suppressed the osteogenic transdifferentiation of VSMCs via regulation of runt-related transcription factor 2 (Runx2). Coimmunoprecipitation (co-IP) and immunoprecipitation (IP) assays confirmed that SIRT6 bound to Runx2. Moreover, Runx2 was deacetylated by SIRT6 and further promoted nuclear export via exportin 1 (XPO1), which in turn caused degradation of Runx2 through the ubiquitin-proteasome system. These results demonstrated that SIRT6 prevented VC by suppressing the osteogenic transdifferentiation of VSMCs, and as such targeting SIRT6 may be an appealing therapeutic target for VC in CKD.
Highlights
Vascular calcification (VC), especially in tunica media, is prevalent in patients with chronic kidney disease (CKD) [1,2,3]
Sirtuin 6 (SIRT6) suppresses osteogenic transdifferentiation of VSMCs via downregulation of Osteogenic transdifferentiation of VSMCs serve a critical role in VC, so we explored the potential role of SIRT6 in this process
Since the osteogenic transdifferentiation of VSMCs highly regulated by Runx2 [9,10], we examined whether SIRT6 regulated VC through Runx2
Summary
Vascular calcification (VC), especially in tunica media, is prevalent in patients with chronic kidney disease (CKD) [1,2,3]. Phosphate (Pi)-induced remodeling of VSMCs are essential for the mineralization of vascular tissue, and are highly regulated by osteogenic transcription factor runt-related transcription factor 2 (Runx, known as core-binding factor subunit α1, CBFA1) [9,10,11,12]. In this context, it is tempting to suggest that treatment strategies are needed to block osteogenic transdifferentiation of VSMCs for preventing or halting the progression of VC. Inhibition of osteogenic transdifferentiation of VSMCs have not been developed, and such approaches are still lacking
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
