Sirtuin-1 and Its Relevance in Vascular Calcification

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.

Astaxanthin Counteracts Vascular Calcification In Vitro Through an Early Up-Regulation of SOD2 Based on a Transcriptomic Approach

“…Important pathways including protein processing and metabolism (endoplasmic reticulum processing, proteolysis, mammalian target of rapamycin (mTOR), and transforming growth factor-β (TGF-β) signaling) were suppressed during astaxanthin treatment, while they were induced by HP ( Figure 4 A); pathways such as calcium, cAMP, and MAPK signaling; cytokine receptor interaction; chemokine signaling; and cytoskeletal regulation were induced during astaxanthin treatment, while they were attenuated by HP ( Figure 4 B). We further focused on pathways that contributed potentially to VC pathogenesis through biologically meaningful connections based on the existing literature [ 10 , 15 , 16 , 17 ], with 79 genes from 8 and 2 positively and negatively enriched pathways, respectively, retrieved ( Figure 4 C). A node plot illustrating the regulatory networks between pairable candidates among all the enlisted genes is shown in Figure 4 D. To explore the strengths of regulatory relationships and identify hub genes, we measured the strengths of each candidate gene within four Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (mTOR and TGF-β signaling, receptor of AGE (RAGE) signaling, and longevity-regulating pathways) with both p -value and q-value < 0.05, using a closeness plot ( Figure 4 E).…”

Superoxide Dismutase 2 (SOD2) in Vascular Calcification: A Focus on Vascular Smooth Muscle Cells, Calcification Pathogenesis, and Therapeutic Strategies

“…Feresin et al previously found that polyphenols from berry extracts could trickle up the expressions of Sod2 in treated VSMCs, decrease ROS severity, and ameliorate VSMC senescence, accompanied by the inhibition of Akt, MAPK, and extracellular-regulated protein kinase (ERK) signaling [ 66 ]. These effects are expected to improve vascular calcification through the intertwined connections between these pathways and calcification pathogenesis [ 44 , 67 ]. Magnesium has also been shown to ameliorate oxidative stress and decrease vascular calcification severity through its effect on multiple pathways, including SM22 regulation [ 68 ].…”

Influence of Resveratrol on the Cardiovascular Health Effects of Chronic Kidney Disease

“…SIRT-1 deacetylases various transcription factors that are involved in lifespan prolongation. The expression of NO synthase is upregulated by SIRT-1, which also upregulates fork head box O to maintain vascular endothelial morphology [ 73 ]. RSV also augments eNOS expression through SIRT-1 activation.…”