Abstract
Vascular calcification (VC) is highly associated with cardiovascular disease and all-cause mortality in patients with chronic kidney disease. Dysregulation of endothelial cells and vascular smooth muscle cells (VSMCs) is related to VC. Sirtuin-1 (Sirt1) deacetylase encompasses a broad range of transcription factors that are linked to an extended lifespan. Sirt1 enhances endothelial NO synthase and upregulates FoxOs to activate its antioxidant properties and delay cell senescence. Sirt1 reverses osteogenic phenotypic transdifferentiation by influencing RUNX2 expression in VSMCs. Low Sirt1 hardly prevents acetylation by p300 and phosphorylation of β-catenin that, following the facilitation of β-catenin translocation, drives osteogenic phenotypic transdifferentiation. Hyperphosphatemia induces VC by osteogenic conversion, apoptosis, and senescence of VSMCs through the Pit-1 cotransporter, which can be retarded by the sirt1 activator resveratrol. Proinflammatory adipocytokines released from dysfunctional perivascular adipose tissue (PVAT) mediate medial calcification and arterial stiffness. Sirt1 ameliorates release of PVAT adipokines and increases adiponectin secretion, which interact with FoxO 1 against oxidative stress and inflammatory arterial insult. Conclusively, Sirt1 decelerates VC by means of influencing endothelial NO bioavailability, senescence of ECs and VSMCs, osteogenic phenotypic transdifferentiation, apoptosis of VSMCs, ECM deposition, and the inflammatory response of PVAT. Factors that aggravate VC include vitamin D deficiency-related macrophage recruitment and further inflammation responses. Supplementation with vitamin D to adequate levels is beneficial in improving PVAT macrophage infiltration and local inflammation, which further prevents VC.
Highlights
The presence of vascular calcification (VC) is highly associated with an increased risk of cardiovascular disease and all-cause mortality [1,2,3]
Sirt1 Abolish Endothelial Cells and vascular smooth muscle cells (VSMCs) Senescence. Senescence of both endothelial cells (ECs) and VSMCs contributes to Vascular calcification (VC) and is implicated in the process of cardiovascular disease
Both canonical and noncanonical Wnt-signaling pathways are involved in the phenotypic transition of VSMCs, and they play important roles in the progression of VC and lead to cardiovascular disease [92,93]
Summary
The presence of vascular calcification (VC) is highly associated with an increased risk of cardiovascular disease and all-cause mortality [1,2,3]. Protein-bound uremic toxin can further aggravate this active calcification process in endothelial and medial layers of the vessel [7]. New concepts indicated that calciprotein particles (CPPs) and matrix vesicles (MVs) participate in passive calcification, which can be triggered by hyperphosphatemia and protein-bound uremic toxin-related inflammatory reactions, and lead to calcification within the medial layer of vessel [8,9,10]. Intimal calcification is generally associated with atherosclerosis, which is an inflammatory dependent process and leads to plaque calcification. Local vessel wall inflammation could be accelerated by circulating immune cells adhering to de-amidated endothelial proteins that enhance the release of inflammatory cytokines and, thereby, the development of atherosclerotic plaque [15]
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