Vascular calcification (VC) encompasses a range of conditions characterized by the abnormal deposition of calcium and phosphorus within the vascular wall. It is increasingly acknowledged as an active and regulated process, akin to bone formation (1). The occurrence of VC involves the participation of various cell types, including macrophages, endothelial cells, and vascular smooth muscle cells (VSMCs), which play an essential role in this process (2). The types of calcification include intimal calcification, mesangial calcification, and valvular calcification (3). Among these, intimal calcification is associated with atherosclerosis (4). Medial calcification, also known as Mönckeberg sclerosis, preferentially occurs along the elastic lamina and is typically identified in the small and medium-sized arteries of the lower extremities. This condition is associated with advanced age, diabetes, and chronic kidney disease (CKD) (5, 6). Increasing evidence suggests a correlation between aging and VC (7). Several mechanisms contribute to VC, including inflammation, endoplasmic reticulum stress (ERS), mitochondrial dysfunction, ferroptosis, cell death, and DNA damage repair (8).

The lysine deacetylase Sirtuin (SIRT) family of proteins comprises a widely distributed group of histone deacetylases found in various cell types. This extensive family consists of seven isoforms, namely SIRT1 to SIRT7 (9). SIRT proteins play crucial roles in cellular resistance, energy metabolism, apoptosis, and senescence (10). SIRT1 and SIRT2 are predominantly expressed in the nucleus and cytoplasm, while SIRT3, SIRT4, and SIRT5 are primarily localized in the mitochondria. SIRT6 and SIRT7 are located in the nucleus (11). Currently, SIRT1, SIRT2, SIRT3, SIRT6, and SIRT7 have been associated with VC. Among these, SIRT1, the most extensively studied isoform, inhibits VC primarily by suppressing endoplasmic reticulum stress (ERS) and promoting DNA damage repair (12, 13), SIRT3 inhibits VCmainly by reducing mitochondrial reactive oxygen species (mtROS) production (14), whereas SIRT6 mitigates VC by enhancing DNA damage repair (15, 16). Additionally, SIRT7 decreases calcification by reducing intracellular reactive oxygen species (ROS) accumulation and inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated oxidative stress (17, 18) (Figure 1).

Inflammation is a crucial immune response that occurs during infection or injury, playing a vital role in maintaining tissue homeostasis under various adverse conditions (19), Furthermore, there is a significant association between the occurrence of VC and inflammation (20). The upregulation of inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, can activate downstream inflammatory pathways and facilitate disease progression (19). Elevated levels of IL-1β in medial arterial smooth muscle contribute to the induction of senescence-associated calcification (20). The IL-1β-induced cellular senescence is contingent upon the upregulation of BMP2, which is necessary for osteoclast transformation and subsequent calcification (21). Furthermore, evidence indicates that inflammatory responses can initiate and precede the osteogenic transformation of VSMCs (22). Nucleotide-binding domain, leucine-rich family-containing, pyrin domain-containing-3 (NLRP3) inflammatory vesicles play a crucial role in the calcification of VSMCs, and the inhibition of NLRP3 inflammatory vesicles has been shown to prevent VC (23). Naringin has been shown to inhibit the activation of NLRP3 inflammatory vesicles by promoting SIRT3-mediated mitophagy, thereby reducing NLRP3 inflammatory activity (24). Furthermore, chronic inflammation is recognized as a significant risk factor for aging and age-related diseases (25). NF-κB, a pivotal signaling molecule in inflammation, plays a critical role in both aging and VC. Elevated glucose and phosphate levels induce senescence and VC in VSMCs while concurrently inhibiting SIRT1 expression (26). SIRT1 can directly interact with NF-κB p65, leading to the deacetylation and subsequent inactivation of NF-κB, which inhibits both senescence and the osteogenic differentiation of VSMCs, thereby mitigating VC (26). Additionally, high phosphorus-induced calcification of VSMCs may be linked to premature cellular senescence and replicative senescence (27).

The endoplasmic reticulum (ER) serves as the primary site for protein synthesis and is a crucial reservoir of calcium ions (Ca²⁺). It plays a significant role in maintaining intracellular protein synthesis and stabilizing Ca²⁺ levels (28). ERS is a protective cellular response that mitigates the agglutination of unfolded proteins by reducing their concentration within the cell, thus preserving the intracellular Ca²⁺ balance. ERS exerts a protective effect by inducing the expression of endoplasmic reticulum molecular chaperones, such as glucose-regulated proteins GRP78 and GRP94 (29). Research has demonstrated that ERS can facilitate the osteogenic differentiation of VSMCs through three pathways: IRE1-XBP1, PERK-eIF2α-ATF4, and ATF6 (30). Additionally, spermidine has been shown to alleviate VC in CKD by upregulating SIRT1 and inhibiting the expression of ATF4 and CHOP in smooth muscle cells (12).

Mitochondria serve as central hubs for energy metabolism and play crucial roles in various biological processes. Abnormalities in mitochondrial function significantly influence the onset and progression of VC, with mitochondrial dysfunction identified as a key contributor to this condition (31). Furthermore, mitochondrial dysfunction and oxidative stress are recognized as critical causative factors and therapeutic targets in heart disease, kidney disease, and diabetes (32, 33). Oxidative stress acts as a significant mediator of VC, particularly in the context of medial calcification (34). Previous studies have demonstrated that the inactivation of SIRT3 results in hyperacetylation of superoxide dismutase 2 (SOD2), thereby exacerbating vascular oxidative stress (35). SIRT3 primarily operates within mitochondria, where elevated production of ROS triggers osteogenic transformation in VSMCs. It has been established that SIRT3 can reduce mitochondrial ROS (mtROS) levels by modulating the downstream regulator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which in turn decreases ROS levels and enhances the expression of SOD2 in VSMCs. This mechanism mitigates mtROS levels and inhibits abdominal aortic calcification and carotid arterial calcification in vitro under conditions of high phosphate-induced VC. The use of the SIRT3 inhibitor, 3-TYP, or the application of small interfering RNA (siRNA) to inhibit SIRT3 resulted in a reduction of PGC-1α-induced upregulation of both SOD1 and SOD2, thereby diminishing the protective effects of PGC-1α against calcification in VSMCs. Clinical investigations have revealed that PGC-1α levels are diminished in calcified femoral arteries of CKD patients. Additionally, in phosphate-induced calcification of human arteries, the upregulation of PGC-1α has been shown to inhibit the formation of calcium nodules, an effect that is negated by SIRT3 inhibitors (14).

Double-strand breaks (DSBs) represent the most severe form of DNA damage response, which is activated upon the occurrence of DSBs and leads to the activation of ataxia-telangiectasia mutated (ATM) protein. This activation results in the dissociation of ATM from its dimeric form, followed by self-phosphorylation at Ser1981, thereby facilitating the completion of DNA damage repair (36). In diabetic patients, the absence of SIRT1 accelerates VC induced by DNA damage. Studies have shown that SIRT1 expression is diminished while markers of DNA damage are elevated in calcified arteries of diabetic patients compared to non-diabetic and non-calcified controls. Furthermore, VSMCs isolated from diabetic patients exhibit increased DNA damage and cellular senescence. In the context of diabetes, the process of DNA damage-induced calcification is accelerated; however, in vitro activation of SIRT1 mitigates this calcification by enhancing the MRN repair complex within the vascular endothelium, highlighting its therapeutic potential for diabetic patients (13). Additionally, existing literature indicates that SIRT6 can inhibit the progression of VC in CKD patients by down-regulating RUNX2. Notably, the specific deletion of SIRT6 in VSMCs promotes VC through the inhibition of DNA damage repair (15, 37).

Insufficient levels of SIRT6 lead to the accumulation of DNA damage, which activates the DNA damage response pathway. This activation subsequently results in the phosphorylation of NF-κB through ATM/ATR kinases, indirectly promoting inflammation, a phenomenon referred to as “inflammaging.” Conversely, SIRT1 inhibits NF-κB, thereby reducing inflammation-mediated oxidative stress, lowering the risk of DNA damage, and indirectly supporting the repair functions of SIRT6. SIRT1 primarily addresses acute stress responses, such as inflammation inhibition, and maintains short-term cellular homeostasis by regulating transcription factors like NF-κB. In contrast, SIRT6 concentrates on long-term genomic maintenance, including DNA repair, and delays the aging process through chromatin regulation. Together, these two proteins form a network via the stress signaling pathway (NF-κB) to collectively counteract the cascade of inflammation, aging, and DNA damage.

Clinical studies have demonstrated that the expression of SIRT6 is significantly lower in patients with CKD compared to healthy individuals, and this expression is negatively correlated with the thoracic aortic VC Agatston score (37). Recent findings indicate that GATA6 contributes to the development of VC by accelerating aging-related arterial calcification in VSMCs, which occurs through the inhibition of SIRT6 activity and the obstruction of DNA damage repair mechanisms. The accumulation of DNA damage is a crucial factor in both aging and osteogenic differentiation within VSMCs. During vascular calcification, SIRT6 expression is diminished, and the knockdown of SIRT6 exacerbates DNA damage during the calcification process in VSMCs, as evidenced by an increase in the expression of γ-H2AX, a biomarker for DNA double-strand breaks. The administration of the DNA repair agent AV-153 effectively repaired DNA damage and mitigated the adverse effects associated with SIRT6 knockdown. Furthermore, SIRT6 positively regulates the expression of phosphorylated ATM (p-ATM), and its function is contingent upon ATM activation for the repair of DNA double-strand breaks and the inhibition of vascular calcification. Additionally, Nkx2.5 enhances GATA6 transcription, while SIRT6 inhibits GATA6 transcription through deacetylation and the promotion of Nkx2.5 degradation (16) (Figure 2).

Currently, among the SIRT family, SIRT1, SIRT3, SIRT6, and SIRT7 have been extensively studied, with SIRT1 being the most well-researched. Notably, SIRT2 is the only member predominantly located in the cytoplasm. Recent studies have demonstrated that colchicine inhibits VC by enhancing the SIRT2-PP2Ac signaling pathway, thereby reducing the activation of NLRP3 (38). This discovery identifies SIRT2 as a novel target for the treatment of VC.

Furthermore, there are currently no relevant reports on the roles of SIRT4 and SIRT5 inVC, although SIRT4 and SIRT5 are primarily located in the mitochondria. SIRT4 plays a critical role in aging-related diseases, primarily by regulating mitochondrial metabolism, inhibiting inflammatory responses, and modulating cell apoptosis and cellular stress responses through its ADP-ribosyltransferase and deacetylase activities (39). SIRT4 may improve VC by regulating oxidative stress and inflammatory responses. It is proposed that SIRT4 reduces oxidative damage in VSMCs by downregulating the activity of mtROS-generating enzymes, such as NADPH oxidase. Additionally, SIRT4 can inhibit the activation of the NF-κB pathway, thereby reducing the release of inflammatory factors, such as TNF-α and IL-6, and delaying the formation of a calcified microenvironment.

SIRT5 exhibits limited deglycase activity and functions as a desuccinylase, demalonylase, and deglutaminase. It primarily regulates protein substrates involved in various metabolic processes, including glycolysis, the tricarboxylic acid cycle, and the urea cycle (40). SIRT5 can modulate key enzymes in the tricarboxylic acid cycle, such as citrate synthase and succinate dehydrogenase, through desuccinylation modifications, thereby maintaining the balance of cellular energy metabolism. During the process of VC, SIRT5 may diminish the osteogenic differentiation tendency of VSMCs by inhibiting glycolysis and enhancing oxidative phosphorylation.

Members of the SIRT family play significant roles in VC. The existing research gaps should not be interpreted as a lack of importance. Through the cross-integration of metabolomics and vascular biology, the functions of SIRT4 and SIRT5 may present new breakthroughs in the future study of the mechanisms underlying VC.

The occurrence of VC involves the participation of multiple factors, primarily attributed to the abnormal deposition of calcium and phosphorus in the vascular wall. This article primarily discusses how the SIRT family can ameliorate VC through various mechanisms, including inflammation, ERS, mitochondrial dysfunction, and DNA damage repair. Recently, some studies have confirmed that ferroptosis can promote VC (64), indicating that metformin may alleviate the development of hyperlipidemia-associated VC by inhibiting ferroptosis (65). Ferroptosis is a form of cell death characterized by iron-dependent lipid peroxidation, regulated by multiple pathways, including redox balance, lipid metabolism, and energy metabolism (66). Metformin enhances autophagy and inhibits abnormal cell proliferation through the AMPK/SIRT1-FoxO1 pathway, thereby mitigating oxidative stress in diabetic nephropathy (67). Previous studies have demonstrated that metformin can increase the expression of SIRT3 and GPX4, significantly elevate the levels of p-mTOR and p-AMPK, and improve polycystic ovary syndrome in mice by inhibiting ovarian ferroptosis (68).

SIRT proteins may serve as crucial intermediates for metformin's inhibition of ferroptosis-related vascular calcification. They play a synergistic role by regulating the antioxidant system, iron metabolism, and cellular phenotype transformation. Future research should concentrate on specific activation strategies for SIRT proteins, such as selective agonists, to enhance the targeted therapeutic effects of metformin.

Hesperidin has been shown to prevent the development of calcific aortic valve disease via the SIRT7-Nrf2-ARE axis (17). Future studies could further investigate the SIRT family's pathways that inhibit VC through ferroptosis. Moreover, the SIRT family influences VC through various signaling pathways, including the Wnt/β-catenin, Runx2, NF-κB, and JAK/STAT pathways, as well as the AMPK signaling pathway. Additionally, the role of the SIRT family in VC is noteworthy, with current research primarily focusing on SIRT1, SIRT2, SIRT3, SIRT6, and SIRT7, while the functions of other SIRT proteins in VC remain to be explored. Clinically, it has been observed that a significant number of patients requiring coronary intervention exhibit multiple calcifications in the vessel walls; thus, investigating methods to prevent and delay the progression of VC is a promising area for future research.