SIRT1 is widely expressed in the vasculature, including the endothelial cells, perivascular adipose tissue, and smooth muscle cells (Man et al., 2019). Due to its antioxidant and anti-inflammatory characteristics, SIRT1’s function in endothelial cell biology has drawn increasing attention in research (Potente et al., 2007; Chen et al., 2013). Mice that had SIRT1 specifically deleted in endothelial cells had a reduced ability to create new capillaries in response to angiogenic stimuli (Potente et al., 2007). Elevated acetylation in heart disease is associated with deceased SIRT1 expression (Gorski et al., 2019). In an animal model (rat), the upregulation of SIRT1 has protective benefits against HF, such as decreased apoptosis and enhanced cell survival and cardiac function (Lin et al., 2020). These beneficial outcomes of SIRT1 are enhanced by eNOS activation and beneficial input processes. The synergy between SIRT1 and eNOS helps preserve endothelial function (Man et al., 2019). In a way that is dependent on NAD, SIRT1 directly binds to eNOS and deacetylates, and activates it. There is an inverse relationship between SIRT1 expression and activity and the acetylation of eNOS (Mattagajasingh et al., 2007).

SIRT1 and eNOS are linked in endothelial cells; according to current research on the basis of their co-localization in the nucleus and perinuclear cytoplasm, together they protect against endothelial cell senescence (Mattagajasingh et al., 2007; Ota et al., 2010). The eNOS is the rate-limiting enzyme for NO (a crucial neurotransmitter and signalling molecule) in the cardiovascular system. Numerous studies have verified that eNOS activation and NO generation may prevent atherosclerosis and reduce the senescence of endothelial cells (Liang et al., 2021; Niu et al., 2023). The primary constituent of caveolae, known as “caveolin-1”, binds to cytoskeletal proteins in an indirect manner, preserving caveolae invagination and preventing eNOS activation (Oliveira and Minshall, 2018). Caveolin-1 expression rises and eNOS activity falls in aged endothelium cells (Powter et al., 2015), and the eNOS-mediated NO generation may be strongly impacted by caveolin-1 delivery and binding capacity. SIRT1 regulates the amount of caveolin-1 expression and eNOS deacetylation as a deacetylase with a tight relationship to long-term extension and age delay. Research has shown that SIRT1 expression markedly declines in aged tissues, but the overexpression of SIRT1 could delay aging (Song et al., 2014; Shi et al., 2020).

However, it has found that ginsenoside (g-Rb1), a traditional Chinese medicine that is one of the main bioactive substances extracted from Panax ginseng, has anti-senescence properties. When g-Rb1 is administered, caveolin-1 expression was suppressed, whereas SIRT1 and eNOS mRNA and protein abundance were increased. Caveolin-1 siRNA also enhances the anti-senescence impact of g-Rb1, but siRNAs that inhibited SIRT1 and eNOS reduced it. SIRT1 siRNA inhibited G-Rb1-enhanced NO generation and lowered caveolin-1 acetylation levels. Caveolin-1 and g-Rb1 siRNAs may both increase NO production as well as lowering the acetylation level of eNOS (Zhou B. et al., 2024). Additionally, Rb1 is important for reducing oxidative stress, controlling autophagy, and preventing apoptosis. Recent studies have indicated that Rbi suppresses the SIRT1–eNOS–NO axis, hence lowering oxidative stress and inflammatory responses and thus consequently delaying the aging process in mice (Zhou et al., 2025). In mice with type 1 diabetes, icariin (flavonoid glycoside) produced from the epimedium protects the arteries by lowering inflammation linked to high-mobility group box 1 (HMGB1). When icariin was given to diabetic rats and HG-stimulated HUVECs, it increased acetylcholine-induced vasodilation in the aorta and decreased the production of pro-inflammatory cytokines such IL-8, IL-6, IL-1β, and TNF-α. Additionally, icariin activates the G-protein-coupled estrogen receptor (GPER) and SIRT1, which work together to suppress HMGB1 production and inflammation brought on by HMGB. Likewise with GPER and SIRT1 inhibitors, icariin’s impact on HMGB1 release, and HMGB1-induced inflammation, specifically, the GPER inhibitor, stopped icariin from activating SIRT1 (Wenhui et al., 2024).

Endothelial cells play a vital role in the heart and vasculature, serving as a vital conduit between the immunological and circulatory systems. Recent studies explored the pivotal role of SIRT1 in mice lacking CR6-interacting factor (CRIF1), SIRT1 in mitochondrial dysfunction, and its potential as a treatment approach for endothelial dysfunction. The CRIF1 protein is essential for oxidative phosphorylation and peptide synthesis. The study was carried out in a mice model (Shin et al., 2013); CRIF1 deletion causes cardiomyopathy, heightened oxidative stress, inflammation, and malfunction of the heart and mitochondria.

All of these issues resulted from endothelial cells’ reduced production of SIRT1 after the deletion of the CRIFI protein. SRT1720 (SIRT1activator) were injected (intraperitoneally) in knockout CRIFI mice, increasing the endothelial eNOS and decreasing oxidative stress and inflammation. This improved heart function and improved decreased zonula occludens-1 (endothelial junction associated protein) (Piao et al., 2021). In addition, it has been found that SIRT1 plays a crucial role in acute cardiac hypotrophy (AMI) by reducing cardiomyocyte apoptosis and MI size and improving cardiac dysfunction. In an animal model with ligation of the LAD coronary artery in the overexpression and control of SIRT1, lentivirus was administrated to the peri-infarcted region. In primary cardiomyocytes (in post-myocardial infarction), the expression of SIRT1 and Phd3 were reduced, while cleaved caspase-3 and Hif-1 α expression increased. Moreover, in hypoxic conditions, the levels of nuclear SIRT1 and cytoplasmic Phd3 decreased, while cleaved caspase-3 and Hif-1 α expression increased, leads to alleviated hypoxia-induced cardiomyocytes apoptosis (Chen et al., 2025).

Additionally, SIRT1 which is abundantly expressed in EC, regulates the angiogenic potential and preserves normal endothelial function (Borradaile and Pickering, 2009; Sanchez-Fidalgo et al., 2012). SIRT1 move among the cytoplasm and nucleus in pathological circumstances to alter a number of molecular signaling pathways that help to shield EC from oxidative damage (Hou et al., 2010). Through deacetylating the tumor suppressor p53, SIRT1 specifically inhibits H₂O₂-induced premature senescence of EC, while it shields blood vessels from hyperglycemia-induced EC dysfunction via down-regulating p66Shc expression and transcriptionally regulating eNOS (Figure 3) [5]. Additionally, through raising its acetylation, the reduced SIRT1 expression in human EC under high-glucose therapy also causes p53 to become activated (Zhou et al., 2011). A number of substances, including resveratrol (Milne et al., 2007; Orimo et al., 2009), ghrelin (Sanchez-Fidalgo et al., 2012), and Rb1 (Togliatto et al., 2015), have been shown to restore SIRT1 activity, specifically in ob/ob mice exposed to hind limb ischemia. Unacylated ghrelin, the most prevalent form of circulating ghrelin, further protects endothelial cells (EC) from ROS imbalance by reducing their in vivo senescence via SIRT1-mediated p53 and H3K56Ac deacetylation (Song et al., 2014). The protective effect of paeonol, a phenolic compound extracted from cortex moutan (tree peony bark), against H₂O₂-induced premature senescence in human umbilical endothelial cells is molecularly elucidated by a reduction in H₂O₂-induced upregulation of H3K14Ac and H4K16Ac, which subsequently enhances p53 proliferation through downregulation (Jamal et al., 2014). Additionally, as the development of senescence occurs, SIRT1 mRNA and protein levels gradually decrease because of oxidative stress, which is linked to CVD risk factors. It has been shown that both these stressors induced senescence in mice and that EC senescence was inhibited by SIRT1 overexpression in vitro studies. Meanwhile, as a stress response, deacetylation of serine/threonine kinase B1 (LKB1) is consistently elevated (Zhou et al., 2011). Angiogenesis and endothelium-dependent vasorelaxation were all compromised in a mouse model of vascular senescence that was produced through genetically deleting exon 4 of SIRT1 in EC (SIRT1-endo-/-) (Vasko et al., 2014).

Furthermore, it has been established that Yin-yang 1 (Yy1) transcription factor is linked to the expression of circulating soluble ST2 isoform (sST2) in infarcted myocardium. This suggests that elevated sST2 levels are associated with a lower pre-release LV ejection fraction and adverse cardiovascular outcomes. The growth of miR-199a-5p during MI enhances ventricular hypertrophy by enriching the amounts of circulating soluble (sST2), whereas the Yy1/sST2 axis was used for biomechanical stretching. SIRT1 expression is increased and P300 protein is rendered inactive by antimiR199a treatment, resulting in Yy1 inhibition as well as reduced sST2 expression in cardiomyocytes. This significantly reversed the cardiac hypertrophy in HF mice (Asensio-Lopez et al., 2021). Further, MiR-323-3p, a gene highly expressed in rat models and CHD patients, is involved in the progression of the disease. Its expression can be downregulated by SRT1, and over-expression or inhibition of it can lead to increased VEC apoptosis, elevated ac-p65 protein expression, and overexpression of proteins involved in the NF-κB signalling pathway (Du et al., 2021). The function of SIRT1 with long-term administration of Mito-Esc to Apoe-/-mice was investigated; its activation increased the levels of human telomerase reverse transcriptase (hTERT), which postponed senescence of endothelial cells (Karnewar et al., 2022). In transcription inhibition, FOXO6 triggered cardiac microvascular endothelial barrier disruption in the OGD/R model in HCMECs. By inhibiting CTRP3 transcription, FOXO6 causes OGD/R, this then triggers SIRT1/Nrf2 signalling to tear down the heart microvascular endothelium barrier (Zheng S. et al., 2024).

Furthermore, SIRT1 play a crucial role as a therapeutic target for CVDs. For example, chronic rmSIRT1 supplementation improves endothelial function and vascular compliance in diabetic conditions by enhancing eNOS activity and suppressing NOX-related oxidative stress. This potentially prevents diabetic vascular disease (Yang K. et al., 2023). High glucose levels in CMEC increased ROS, malondialdehyde, and apoptotic cell percentage, it is reversed via the administration of RSV through AMPK/SIRT1 activation (Li et al., 2023). Endothelial dysfunction is prevented by dapagliflozin A (SGLT2) inhibitors via SIRT1 activation, and it is ameliorated by restoring eNOS activity, NO bioavailability, and decreased ROS production (Zhou Y. et al., 2023). In HF mice without diabetes, dapagliflozin, an inhibitor of sodium-glucose-linked transporter 2, decreased EndMT brought on by ISO via deacetylating and breaking down NICD by SIRT1 (Wang W. et al., 2023). DAPA has been shown to activate the SIRT1/PGC-1α pathway, which improves endothelial cell mitochondrial function in obese mice (He et al., 2022a). Moreover, homocysteine (a risk factor for CVDs) suppressed STS (a hydrophilic derivative of tanshinone IIA) by activating signalling pathways SIRT1/NRF2/HO-1, NNMT/MMA, and AKT/MAPKs (Zhou Z.-Y. et al., 2023). SIRT1 could potentially promote the inhibition of NLRP3 inflammasome in ECs by L-arginine (semi-essential amino acid) (Zhang M. et al., 2021). Lycopene mitigates oxidative damage in human VECs via activation of the SIRT1/Nrf2/HO-1 pathway, thereby reducing oxidative stress, ROS, cell adhesion, inflammation, and apoptosis (Guo et al., 2023). A trace element called selenium protects against cardiovascular damage by controlling the SIRT1/p53 and Cyt-c/Cas-3 pathways (Ilhan et al., 2023). Naringenin (Nar), a bioactive flavanone compound, activates the AMPKα/SIRT1 signalling pathway, restoring mitochondrial Ca²⁺ and decreasing ROS production as well as upregulating eNOSactivity, increasing NO production, and improving ED (Li et al., 2021). Moreover, melatonin (hormone) regulates the AMPK/SIRT1 pathway, thus attenuating HG-induced CMEC STZ-induced cardiac dysfunction, oxidative stress, and apoptosis injury (Wang B. et al., 2021). One important treatment target for Kawasaki disease (KD) is the SIRT1/NF-κB/p65 pathway, which is linked to cardiac dysfunction as well as inflammatory injury to myocardial cells and HCAECs by inhibition of pyroptosis (Yang Y. et al., 2024).

Endothelial dysfunction, shown by decreased endothelium-dependent vasorelaxation, is the initial cause of atherosclerosis (Gimbrone Jr and García-Cardeña, 2016). Enhanced oxidative stress, inflammation, reduced autophagy, and decreased NO generation by eNOS and its signalling pathway are among the established causes of atherosclerosis linked to endothelial dysfunction (Donato et al., 2015). In addition to endothelial failure, atherogenesis, which is linked to inflammation and oxidative stress, includes the development of foam cells in the artery walls and the activation and infiltration of immune cells such as macrophages and monocytes (Moore et al., 2013). Additionally, prior research has shown that autophagy in monocytes as well macrophages is essential in the pathophysiology of atherosclerosis by lowering inflammation and oxidative stress linked to insulin resistance. Both hepatic and adipose tissues contribute directly or indirectly to the pathogenesis of atherosclerosis and vascular aging (Lim and Meigs, 2014). Additionally, SIRT1 expression was reduced in HUVECs stimulated with LPS and ATP. The SIRT1 activator inhibited the expression of monocyte chemotactic protein-1 (MCP-1) and C-reactive protein (CRP), whereas SIRT1 knockdown resulted in notable increases in MCP-1 and CRP levels in HUVECs stimulated with LPS and ATP. SIRT1 deficiency enhanced NLRP3 inflammasome activation and the ensuing caspase-1 cleavage, while the NLRP3 siRNA prevented NLRP3 inflammasome activation in HUVECs treated with both ATP and LPS. The NLRP3 inflammasome significantly decreased MCP-1 and CRP production in HUVECs, and the SIRT1 activator therapy decreased MCP-1 and CRP expression levels in collared arteries and IL1-β blood levels (Li Y. et al., 2016). The interaction between these genes was determined using bioinformatics analysis and the dual luciferase reporter gene experiment. The ac-p65 protein, which is linked to the NF-κB signaling pathway, and miR-323-3p were both expressed at higher levels in blood samples from patients with mild VEC or CHD atherosclerosis. Increased VEC apoptosis, ac-p65 protein expression, and levels of NF-κB signalling pathway proteins were the outcomes of overexpressing mir-323-3p or suppressing SIRT1 (Kang, 2023). It has been shown that dihydromyricetin (DMY), a flavonoid from Ampelosis grossedentata, has potential as a therapeutic treatment for atherosclerosis. Deficient SIRT1 has an anti-atherosclerotic role through M1 polarization and regulates the TIMP3/ADAM17 pathways (Jia et al., 2024). In ApoE-/-mice, naringenin treatment increased dyslipidemia, the formation of atherosclerotic lesions, and vascular senescence. It affected vascular senescence and atherosclerosis by activating SIRT1, deacetylating FOXO3a, and modulating PGC1α (Wang J. et al., 2023).

Additionally, the presence of SIRT1 and HAND2-AS1 (antisense-RNA) in plasma from individuals with atherosclerotic plaques and macrophages was derived from THP-1 stimulated by ox-LDL declination (Ma L. et al., 2022). Steroids are the principal treatment for Lupus nephritis (LN), whereas panax notoginseng saponins (PNS) efficiently ameliorate SR and enhance dyslipidaemia in LN through the regulation of the SIRT1/PPARγ signalling pathway (Xu et al., 2025). The Laminaria japonica polysaccharide (LJP61A) regulates autophagy behavior by up-regulating SIRT1 and FoxO1 and reducing atherosclerosis in HFD-induced LDLr-/-mice; this effect had an effect on siRNA and FoxO1 inhibitors (Li X.-Y. et al., 2022). Additionally, CTRP9, a protein present in the peripheral blood of healthy donors, is essential for lowering cell viability, inhibiting autophagy, and preventing lipid buildup brought on by ox-LDL. It maintains SIRT1 protein levels, upregulates USP22, promotes autophagy and reduces lipid accumulation, leading to a protective effect against atherosclerosis progression (Zeng et al., 2024). The La Ribonucleoprotein Domain Family Member 7 (Larp7), a protein that promotes senescence by decreasing SIRT1 function, led to the development of atherosclerosis in ApoE-deficient mice when subjected to a high-fat diet. Overexpression reduces p16 positive senescent cells in aortic lesions, decreases pro-inflammatory macrophages and SASP factors, and reduces atherosclerotic lesions in HFD-fed ApoEKO (Larp7tetO) mice to prevent atherosclerosis (Yang P. et al., 2024).

In addition to atherosclerosis, diabetes, heart failure, age, hypertension, and other conditions affecting the vascular system, oxidative stress is a major cause of CVDs. The accumulation of ROS, which regulates cellular processes, is linked to negative outcomes in CVD. ROS include free radical species, lipid radicals, superoxide anion, nitric oxide, and chemical species with high oxidizing potential. Further, Geniposide (GE), an iridoid glycoside from Gardenia Jaminoides, was found to promote Nrf2 transcriptional activation in HFpEF mice, alleviate oxidative stress in H9c2 and HL-1 cells, and reduce oxidative damage brought on by H2O2 using the MMP2/SIRT1/GSK3β pathway (Han Y.-L. et al., 2024). In Oa-treated VSMCs, SRT120 reduced mtROS, increased SIRT1 and PGC-1α deacetylation, decreased mtDNA damage, and sped up mitochondrial repair in OA-induced dysfunction (Sung et al., 2024). A member of the CTRP family, C1q/TNF-related protein 6 (CTRP6), has been shown to reduce CTRP6 expression in the plasma of heart failure patients’. Its AMPK/SIRT1/PGC-1α signaling pathway activation restored mitochondrial homeostasis, which slows the development of heart failure by raising ATP levels and lowering ROS levels (Fan et al., 2024).

Moreover, the overexpression of miR-135 in human and mice cardiac fibroblasts enhances oxidative stress, proliferation, and fibrosis, while inhibiting mitochondrial activity and mediating mitochondrial oxidative respiratory function via SIRT1 to modulate atrial fibrosis (Ding et al., 2024). ACE2 has shown to be important in the development of sepsis-induced cardiomyopathy (SIC) in C57BL/6 mice. Treatment options include ACE2 inhibitor MLN-4760 and its activator diminazene aceturate (DIZE); DIZE improved mortality, cardiomyocyte apoptosis, oxidative stress, inflammatory response, and cardiac dysfunction by encouraging MasR-SIRT1-mediated mitochondrial biogenesis, whereas ACE2 inhibitor MLN-4760 exacerbated SIC by preventing MasR-SIRT1-mediated mitochondrial biogenesis (Wan et al., 2024). For ischemic stroke patients, the SIRT1-BMAL1 pathway is crucial for controlling oxidative stress, according to the expression levels and affecting factors of these pathways. Moreover, ischemic stroke patients have higher levels of oxidative stress and inflammatory markers, such as IL-6, TNF-α, MDA, and SOD, than non-stroke patients. Certain subgroups of ischemic stroke patients had the lowest expression levels of SOD, BMAL1, and SIRT1, whereas other subgroups had the highest levels of MDA, IL-6, and TNF-α (Shi J. et al., 2024). When pathological cardiac hypertrophy in mice was studied, the function of mitochondrial protein homeostasis was examined. Transverse aortic constriction (TAC) was shown to produce less hypertrophy, mitochondrial dysfunction, and oxidative stress damage when C1q-tumor necrosis factor-related protein-3 (CTRP3) was overexpressed. The regulatory protein ATF5 is essential for UPRmt, while SIRT1 was identified as a possible downstream effector molecule. Additionally, during TAC, overexpression of CTRP3-activated UPRmt reduces hypertrophy. By signaling UPRmt via the SIRT1/ATF5 axis, CTRP3 decreases oxidative stress damage and mitochondrial dysfunction (Shi L. et al., 2024).

Extrinsic and intrinsic variables collaborate in influencing the aging rate and aging phenotype. Decline in organ function and heightened disease susceptibility associated with aging underscores the therapeutic importance of identifying the mechanisms governing this process. It has been shown that moderate overexpression of SIRT1 decreased age-dependent apoptosis/fibrosis, senescence markers, cardiac hypertrophy, and cardiac dysfunction. In contrast, high levels of SIRT1 enhanced hypertrophy and apoptosis, thereby causing cardiomyopathy (Finkel, 2005; Alcendor et al., 2007). Cellular senescence, known as the permanent cell cycle, slows down and can be triggered by stresses like aging, ROS, and DNA damage, while in several cardiac types senescence is linked to numerous CVDs, including atherosclerosis, cardiomyopathies, valvular disease of the heart, and arrhythmias (Chen M. S. et al., 2022).

Moreover, Mito-Esc plays a key role in aging mice; its treatment prevents lipid profile formation and improves blood pressure as well as atherosclerotic plaque formation. Activating SIRT1 also raises the amount of human telomerase reverse transcriptase, delaying the senescence of endothelial cells (Karnewar et al., 2022). It has been shown that Metoprolol (β1 receptor blocker) plays a key role in aging; cardiomyocytes are shielded against cellular senescence caused by arginine vasopressin (AVP). It was found to be effective in reducing DNA oxidation, decreasing senescence-associated β-Gal positive cells, and improving telomerase activity. Furthermore, in cardiomyocytes, metoprolol decreases SIRT1 activity, intracellular NAMPT activity, and the NAD⁺/NADPH ratio (Li Q. et al., 2022). SIRT1 is crucial for preventing damage to myocardial contractility since its deletion in young mice’s hearts results in decreased cardiomyocyte contractility and aging-like cardiac dysfunction (Zhang J. et al., 2021). Hydrogen sulphide (H₂S) has been shown to control pathophysiological processes in the body, such as aging, which is linked to changes in the heart’s structure and function. In the cardiac tissues of elderly rats and cultured aged cardiomyocytes, exogenous H₂S upregulates the SIRT1-PINK1-parkin pathway, preventing cell death, mitochondrial damage, and oxidative stress while promoting mitophagy (Hao et al., 2022). A novel adipokine known as Isthmin-1 (ISM1) plays a crucial role in aging-related cardiac dysfunction; overexpression of the ISM1 in aging mice mitigates insulin resistance via promoting glucose uptake. ISM1 is essential for reducing myocardial inflammation, cellular aging, and dysfunction in natural as well as in accelerated cardiac aging. It also promotes glycolysis and activates SIRT1 via increasing glucose uptake, this leads to increased SIRT1 activity by O-GlcNAc modification (Hu et al., 2024). In addition, a novel DPP-4 inhibitor anagliptin, was investigated as a potential therapeutic in atherosclerosis, and its treatment improved TNF- α, IL6, and MCP-1 secretion in VSMC, reduced telomerase activity, and reversed upregulated SIRT1 in IL-1 β treated cells. SIRT1 suppression, however, eliminated the VSMCs’ defense against cellular senescence (Zhao et al., 2021).

Additionally, via phosphorylating the SMAD complex, ST2 enhanced TGFβ signaling in vitro, which in turn activated mouse cardiac fibroblasts (MCFs) and suppressed cellular senescence via the signaling pathway of SIRT1/p53/p21 (Tan et al., 2023). ANE can delay cell senescence by inhibiting PARP1 activity, thereby encouraging SIRT1 activity and increasing NAD⁺ release. This approach is a useful anti-aging tactic (Zhao L. et al., 2024). Research has shown that the natural flavone acacetin counteracts the effects of D-galactose-induced myocardial senescence in C57/BL6 mice and H9c2 rat cardiac cells. Oral acacetin administration also improves heart function in animals with accelerated aging by retaining mitochondrial function and boosting mitophagy (Hong et al., 2021). Moreover, doxorubicin-induced subacute senescent cardiomyocytes showed increased expression of markers P21, SA-β-gal, Suv39h1 (histone lysine methyltransferase), and H3K9Me3, suggesting that downregulation of Suv39h1 reversed the decline of mitochondrial membrane potential. The positive rate of SA-β-gal was lower in the sh-Suv39h1 group, leading to cell senescence inhibition (Yang and Liu, 2024). Endothelial progenitor cells (EPCs) undergo senescence due to TMAO, a process that is associated with age-related diseases. When EPCs were treated with TMAO, Lyc, siAMPK, and siSIRT1, the protective effect was reduced. Lyc, in particular, reduces TMAO-induced EPC senescence via the AMPK/SIRT1 pathway (Liu et al., 2025). A GLP-1 receptor agonist called ligarglutide (LIR) controls blood sugar levels and reduces vascular stress to help manage diabetes, while also preventing diabetic CVDs by targeting high-glucose induced endothelial cell senescence via the SIRT1-p53/65 signaling pathway (Zhong et al., 2025).

SIRT1 has been shown to control fat accumulation by blocking PPARγ (Picard et al., 2004), enhancing insulin sensitivity, lowering inflammation (Yoshizaki et al., 2010), and restricting preadipocyte hyperplasia via C-Myc deacetylation (Abdesselem et al., 2016). There are SIRT1-dependent biochemical pathways linked to obesity and adipogenesis. For example, nicotinamide mononucleotide adenylytransferases (NMNATs) are enzymes that convert NMN into NAD+, which is required for SIRT1 activity. Notably, lower PARP-1 activity during the early phases of differentiation led to a de-repression of CEBPβ activity, which stemmed from reduced nuclear NAD⁺ levels (Luo X. et al., 2017). Studies have looked into NAD⁺ detection probes that target particular cellular compartments and discovered that cytoplasmic NAD⁺ production from NMN was enhanced by cytosolic NMNAT-NMAT2 induction. This initiated a sequence of events that facilitated 3T3-L1 differentiation by lowering nuclear NAD⁺ levels, inhibiting PARP-1 activity, and de-repressing CEBPβ (Ryu et al., 2018). Adipocyte respiration as well as mitochondrial biogenesis depends on SIR1; it affects adipocytes’ SREBF1c and PPARα signaling as well. NMNAT2 expression is likewise stimulated by NMN via SIRT1 during 3T3L-1 development, but it may be inhibited. Leptin, SIRT1, and PGC-1α expression levels increase when NAD⁺ booster NMN is added to preadipocytes during differentiation, although pro-fibrotic collagen levels decrease (Majeed et al., 2021).

Cardiometabolic disorders, including obesity and T2D, are characterized by the dysregulated systemic as well as organ-specific metabolic profiles and linked to elevated cardiovascular risk (Chen Z. et al., 2022; Costantino et al., 2023). These disorders elevate mortality and morbidity rates, while also straining resources and healthcare systems. The metabolic cardiomyopathy MCM is an important condition within the array of cardiometabolic problems, due to its correlation with the onset of heart failure and mortality (Nishida and Otsu, 2017). MCM is characterized via cardiac hypertrophy and dysfunctional remodeling, occurring without coronary artery disease or hypertension, while a notable aspect of MCM is the altered lipid singling that promotes fatty acid absorption, leading to intramyocardial lipid buildup and lipotoxic injury (Costantino et al., 2019; Suffee et al., 2022). FA-induced lipotoxicity adversely affects cardiomyocytes, inducing apoptosis and elevating stiffness, which leads to a reduction in contractile function (Karbasforooshan and Karimi, 2017). These events are essential for the initiation as well as advancement of MCM and predispose individuals to structural and functional alterations that culminate in HFpEF (Jia et al., 2018; Tan et al., 2020). The db/db mice were compared to their db/+ heterozygous littermates; the mice were given intraperitoneal rSIRT1 for weeks. Metabolic cardiomyopathy (MCM) is a disease in which fat buildup in the heart results in cardiac failure with intact ejection fraction. The H9c2 cardiomyocytes exposed to hyperglycemia served as a model of MCM in vitro, and cardiac ultrasonography was utilized to evaluate cardiac function and obtain left ventricular samples. Through improving diastolic performance, fractional shortening, and left ventricular ejection fraction, the rsirt1 therapy maintained cardiac performance and restored cardiac SIRT1 levels. Additionally, it altered the cardiac lipidome by inhibiting the expression of genes linked to lipid transport, metabolism, and inflammation.

PPARG-related genes and intramyocardial triacylglycerols were shown to be greater in people with lower cardiac expression levels of SIRT1 (Majeed et al., 2021). It has been shown that ginsenoside Rc, a substance that targets the SIRT1 signaling system, enhances mitochondrial biogenesis and glucose aerobic metabolism, which increases resistance to cardiac and neurological damage. It was verified that Rc’s interaction with SIRT1’s residue sites promoted its activation. Ginsenoside Rc enhances mitochondrial biogenesis, increases the amounts of complex II-IV of the electron transport chain in neurons and cardiomyocytes, and raises the levels of mitochondrial pyruvate carrier I/II, ATP synthesis, glucose absorption, and hexokinase I/II. Additionally, by reducing PGC1α acetylation through SIRT1 restoration, it activates the PGC1α pathway to induce mitochondrial biosynthesis and decreases mitochondrial damage and apoptosis. This results in SIRT1 activation, which enhances energy metabolism and enhances cardiovascular and neuroprotective processes in both healthy and injured individuals (Huang et al., 2021).

Quercetin pretreatment can reduce ROS and oxidative stress damage in human cardiomyocytes, increase mitophagy, and regulate TMBIM6 expression and endoplasmic reticulum stress, however, transfection with SIRT1 counteracts these protective effects. Quercetin is expected to prevent oxidative stress damage brought on by H/R and control mitophagy and ER stress via SIRT1/TMBIM6 (Chang et al., 2021a). Another study examined the vascular endothelium in obese mice and HUVECs in vitro as a result of sodium-dependent glucose transporters 2 inhibitor DAPA. DAPA reversed the effects of vascular endothelial damage in obese mice and reduced the effects of palmitic acid (PA) on angiogenesis and apoptosis in HUVECs. In addition to enhancing mitochondrial membrane potential, viability, energy metabolism, and biogenesis and improving the structural damage brought on by PA, it also triggered the SIRT1/PGC-1α signaling pathway (He et al., 2022a). Another study showed that hyperglycemia can be averted via DAPA through AMPK/SIRT1 pathway activation; this potentially could become the treatment target for HG-induced damage to endothelial cells (Faridvand et al., 2022).

Atrial stiffness and hypertension are often considered prevalent age-related conditions, since their incidence escalates with advancing age (AlGhatrif et al., 2013; Rosano et al., 2013). Arterial stiffening indicates the progressive fragmentation and depletion of elastin fibers, together with the deposition of more rigid collagen fibers in the media of major arteries (Coutinho et al., 2011; Sun, 2015). It transpires independently of atherosclerosis and serves as an autonomous predictor in cardiovascular outcomes (Kaess et al., 2012). Aortic stiffness elevated the systolic blood pressure and the onset of hypertension, demonstrating the correlation among large-artery stiffness and hypertension development (Sun, 2015). It has been shown that the expression and activity of SIRT1 reduces in aortic endothelial as well as mice smooth muscle cells of KL+/−, indicating that klotho deficiency downregulates SIRT1. Moreover, when administered with a selective SIRT1 activator known as SRT1720, arterial stiffness and hypertension were eliminated via Klotho loss in mice muscle cells KL+/−. SRT1720 reversed the klotho depletion which is correlated with substantial reductions in the activity of AMPKα and eNOS in aortas. Additionally, Klotho deficiency increased NADPH oxidase activity, superoxide production, and collagen expression and accelerated elastin disintegration in aortic media (Gao et al., 2016). In another investigation, Klotho deficiency was shown to worsen diastolic dysfunction, exercise intolerance, and cardiac hypertrophy. While the deficiency also enhanced cardiac capillary densities, these abnormalities were mitigated by sKL therapy. The SIRT1 signaling pathway, via the downstream mechanisms of Klotho, promotes diastolic function. Additionally, the reduced Klotho levels were associated with SIRT1insufficiency, however, in mice’s aged hearts, sKL treatment restored SIRT1 expression and alleviated the activation of DNA damage response system. sKL supplementation, then, may be seen as a potential treatment approach for addressing HFpEF in aged mice (Chen and Sun, 2019).

Moreover, angiotensin II (Ang II) elevated expression of SIRT1 via oxidative stress and growth factor receptor-mediated MAP kinase/Akt signaling pathways. These augmented the production of Giα proteins as well as cell cycle proteins, leading to the hyperproliferation of VSMCs. ANG II influences the control of several physiological activities; this includes the proliferation and hypertrophy of VSMCs via the overexpression of Giα proteins (Hossain et al., 2021). Further, it has been shown that in young, healthy arteries, the expression of circ-SIRT1 was abundantly expressed; while in older arteries and the neointima of mice and humans VSMC cells, its expression was lower. The overexpression of circ-SIRT1 reduced neointimal hyperplasia in vivo and postponed Ang II-induced VSMC senescence in vitro. While at transcriptional as well as post-translational modulation levels, circ-Sirt1 suppressed p53 activity, and it facilitated the SIRT1-mediated p53 deacetylation and inactivation via interacting and holding p53 to prevent its nuclear translocation (Kong et al., 2021). Another study showed that, when neointimal formation occurred after damage, circ-SIRT1 decreased, as did VSMC cells subjected to platelet-derived growth factor BB (PDGF-BB). The localization of circ-SIRT1 in the cytoplasm of VSMCs, where it interacted with c-Myc, (a protein linked to VSMC proliferation), exerted an inhibitory influence on c-Myc activity (Huang et al., 2022).

SIRT2 is essential to biological functions as it acts on the deacetylation of target proteins; its levels reduce with age and various circumstances, resulting in cardiovascular failure. (Table 2; Taneja et al., 2021; Alhasaniah et al., 2024). Sirt2 is essential for AMPK activation, which limits myocardial hypertrophy brought on by age and Ang II. Additionally, it was utilized to target treatment strategies for aging and stress-induced heart hypertrophy (Tang et al., 2017; Lu et al., 2024). EPC-derived exosomal (circ_0018553) reduced Ang II-induced cardiac hypertrophy by effectively regulating the miR4731/Sirt2 signaling pathway (Zuo et al., 2023). Sirt2, a nuclear protein, modulates the cell cycle by binding and deacetylating FOXO1, which becomes significantly acetylated during autophagy triggered by serum deprivation or oxidative stress. The dissociation of cytosolic FOXO1-SIRT2 complexes results in heightened acetylation of FOXO (Jiang et al., 2023). The absence of SIRT2 complexes results in heightened acetylation of FOXO (Sola-Sevilla and Puerta, 2024). In the absence of SIRT2, acetylated FOXO1 interacts with Atg7, which is essential for starting the autophagic process (Hwang et al., 2023). The studies demonstrates that SIRT2 functions as a unique negative regulator of the NFAT TF, ameliorating heart failure in SIRT2-deficient mice (Bouhamida and Chaudhry, 2023). Furthermore, following an acute cardiac hypotrophy, plasma SIRT2 levels may be a biomarker for heart failure and other serious adverse cardiovascular events (Han R. et al., 2024).

Human SIRT3 (hSIRT3) has two isoforms, and its location is highly debated, localized either in the cytoplasm and nucleus. The longer isoform a full-length protein that is 44 kDa long (Adolph, 2023). When mitochondrial matrix processing peptidase (MPP) cleaves the N-terminal mitochondrial localization sequence (MLS) of SIRT3, a 28 kDa isoform of hSIRT3 is produced. The longer isoform is then processed by proteases into a functionally active mitochondrial deacetylase (He et al., 2024). SIRT3 is an essential mitochondrial enzyme implicated in energy balance, cardiac remodeling, and heart failure. Its expression reduces with aging, cardiovascular conditions, and metabolic disorder (Table 2; Zhang et al., 2024d). SIRT3 protects the heart against hypertrophy, cardiac dysfunction, and stress-induced cellular apoptosis. Clinical investigations indicated that coronary microcirculation abnormalities were seen among individuals with heart failure and a maintained ejection fraction (Liu et al., 2023; Zhang et al., 2024d). According to in vitro studies, the expression of SIRT3, PPAR-α, and eNOS proteins was elevated in a concentration-dependent way by high-glycemic (HG) levels (Tsetegho Sokeng, 2019; Liu L. et al., 2021). HAECs had lower levels of iNOS expression, while overexpression of SIRT3 in cells inhibited iNOS expression. SIRT3 is associated with the development of atherosclerosis among individuals with type 2 diabetes via upregulating eNOS and PPAR-α (Gong et al., 2022). In endothelial cells, SIRT3 promotes the anti-inflammatory, anti-autophagic, and antioxidant effects of PCSK9 inhibitors, also decreasing LDL. These inhibitors imply that SIRT3 may be a modulator of this pleiotropy (D'Onofrio et al., 2023). In order to improve vascular resilience and protect the human microcirculation from stress, SIRT3 may be a suitable therapeutic target due to its crucial role in compensatory signaling during flow in human arterioles (Jobe et al., 2024). Through the activation of promoting autophagosome formation, EMPA reduces heart damage in obese mice by promoting autophagosome membrane elongation via ATG4B/ATG5 and starting autophagy via AMPK/Beclin1 (Luo et al., 2024). When rats were fed high-salt diets, it was shown that hypertension may cause atrial fibrillation (AF) and alteration of lipid metabolism; AF sensitivity was increased when the SIRT3/AMPK signaling pathway was inhibited (Wang X.-H. et al., 2024).

The heart, kidneys, brain, and liver all have the mitochondrial sirtuin SIRT4, which is an effective ADP-ribosyltransferase on histones and bovine serum albumin but lacks NAD⁺ dependent deacetylase activity (Poulose and Raju, 2015). SIRT4 exerts protective effects via its anti-apoptotic function and regulates insulin synthesis, mitochondrial gene expression, and fatty acid oxidation. SIRT4 serves a contentious function within the cardiovascular system; based on the situation, it can be beneficial or detrimental. In mice given ANG2, it causes hypotrophy, fibrosis, and heart failure (Table 3) and it stimulates mitochondrial fusion in SIRT4-transfected HEK293 and fibroblast cells, inhibits mitophagy through linking to the protein ocular atrophy 1 (OPA1), and increases ROS buildup by connecting with SIRT3, which stops SIRT2 from activating (Han et al., 2019; Eid et al., 2021). ATP synthesis in mammalian cells is linked to SIRT4 expression. For this process, the adenine nucleotide translocase 2 (ANT2) facilitates the entry of ADP into the mitochondria and the exit of ATP. Crucially, ANT2 must be deacetylated for this transport to function effectively. In the cardiovascular system, SIRT4 facilitates mitochondrial fusion in SIRT4-transfected HEK293 cells and fibroblasts, prevents mitophagy by binding to the protein known as ocular atrophy 1 (OPA1), and increases ROS buildup through its relationship with SIRT3, which stops it from activating SOD2 (Zullo et al., 2022). SIRT4 modulates myocardial hypertrophy by influencing transcription levels, while MiR-497 targets SIRT4, and its overexpression can inhibit SIRT4 both in vitro and in vivo (Zhang and Ni, 2021). Furthermore, by affecting the miR-93-5p/SIRT4 pathway, the lncRNA MALAT1 may reduce cardiac hypertrophy. MALAT1 also regulates SIRT4 production by degrading miR-93-5p (Xu et al., 2023). It has recently been shown that in male mice (C57BL/6 sirt4-Tg) treated with Ang II, the Sirt4-mediated hypertrophic response was inhibited by manganese porphyrin, a SOD mimic (Luo Y.-X. et al., 2017). By raising ROS levels, Sirt4-mediated hypertrophic response was inhibited through the development, fibrosis, and cardiac dysfunction, pointing to a possible involvement for Sirt4 in pathological cardiac hypertrophy (Ramachandra et al., 2021). Additionally, overexpression of SIRT4 reduces myocardial infarct size and serum creatine phosphokinase levels, while siRNA depletion amplifies these parameters. The protective functions of SIRT4 against cardiac ischemia-reperfusion damage are associated with maintained mitochondrial activity and reduced myocardial apoptosis. It may improve myocardial ischemia-reperfusion damage by modulating mitochondrial activity and apoptosis, yielding therapeutic advantage (Christidi and Brunham, 2021). SIRT4 overexpression reduces DIC by improving cardiac function and lowering cardiomyocyte autophagy and apoptosis. It may also provide protection against DIC by inhibiting Akt/mTOR-dependent autophagy (He et al., 2022b). The oxLDL administration decreased SIRT4 expression in HUVECs, influencing cell mortality and proliferation, and overexpression of SIRT4 reduced cellular mortality and enhanced proliferation. By obstructing PI3K phosphorylation and p65 NF-κB expression, it blocked the PI3K/Akt/NF-κB pathway, enhancing HUVEC viability, diminishing inflammatory cytokine production, and suppressing the signaling pathway (Tao et al., 2019).

Metabolic activities such as the Krebs cycle, glycolysis, oxidation, fatty acid, and urea cycle are regulated by mitochondrial SIRT5 (Bringman-Rodenbarger et al., 2018). It has been shown that mice with sirt5 silencing had lower expression levels of the fibrinolysis inhibitor PAI. The absence of Sirt5 in the diabetic heart results in diminished fatty acid oxidation but does not influence fatty acid absorption capacity, leading to the buildup of fatty acid intermediate metabolites such as medium and long-chain fatty acyl-carnitines. The functional succinylated substrate mediator of SIRT5 is recognized to be CPT2, an enzyme that catalyzes the conversion of fatty acyl-carnitines into fatty acyl-CoA. The absence of SIRT5 causes Lys424 in CPT2 to become succinylated, which in turn causes the accumulation of fatty acyl-carnitines and the inactivation of its enzymatic activity. The CPT2 (K424R) mutation mitigated the disruption of fatty acid oxidation and lipid accumulation brought on by SIRT5 deletion, indicating that SIRT5 and CPT2 could be therapeutic targets for diabetic heart disease (Wu et al., 2024). Cardiomyocyte apoptosis brought on by oxidative stress is mostly controlled by SIRT5, and pharmacological treatments that target SIRT5 expression may help repair heart damage brought on by oxidative stress (Liu et al., 2013b). Additionally, it has been shown that quercetin, a component in medicinal plants, provides therapeutic benefits against heart conditions. Quercetin has demonstrated the ability to enhance cardiac function and reduce myocardial fibrosis in animal models of heart failure and myocardial fibrosis by improving mitochondrial energy metabolism and modulating mitochondrial fusion/fission and biosynthesis; however, cell survival was affected as it encouraged SIRT5 expression to desuccinylate IDH2, and si-SIRT5 treatment eliminated quercetin’s protective impact on cellular survival (Chang et al., 2021b). In obese mice, SIRT5 plays a key function in lipid metabolism and the browning of white adipose tissue. The absence of SIRT5 elevates UCPI succinylation, leading to diminished capacity and compromised cold tolerance; the SIRT5-C/EBPβ axis governs energy equilibrium and metabolism associated with obesity (Zhai et al., 2024).

SIRT6 and SIRT7 significantly influence cardiovascular diseases by regulating several pathways (Table 4). The overexpression of Nrf2 affects the progression of CAD by decreasing NF-kB expression and enhancing the production of antioxidant genes (Divya et al., 2024). NF-kB causes endothelial dysfunction by increasing the production of inflammatory cytokines (Casper, 2023). The Nrf2 pathway can control SIRT6 and NF-κB, preventing CVDs by reducing the generation of ROS and reducing inflammation by downregulating NF-kB transcription (Divya et al., 2024). Overexpression of SIRT6 preserves telomere integrity, delays senescence, and decreases expression of inflammatory cytokines. Endogenous SIRT6 deacetylase plays a key role in VSMC senescence and atherosclerosis (Grootaert et al., 2021). A recent study has shown that, during I/R, SIRT6 is essential for controlling OS and myocardial damage (Liu G. et al., 2021 SIRT6 plays a crucial role in preventing hypertension and its complications. It controls ACE2, possibly by reducing nuclear p-ATF2 accumulation in CC-induced endothelial dysfunction, a known risk factor for hypertension (Zheng Z. et al., 2021). Additionally, SIRT6 maintains endothelial function and prevents hypertension through Nkx3.2-GATA5 signaling (Guo et al., 2019). It was shown that CMECs treated with HG+PA had significantly lower SIRT6 expression, which exacerbated DCM. Sirt6-KOEC exacerbated DCM by decreasing cardiac function and increasing perivascular fibrosis and cardiomyocyte hypertrophy; SIRT6 is linked to EndMT via the Notch1 signaling pathway (Zhang et al., 2020). According to study findings, cholesterol crystals (CCs) have the ability to decrease eNOS levels, increase adhesion molecules, and endocytose ECs (Jin et al., 2020). They also inhibit the production of SIRT6, which might decrease endothelial dysfunction (He Y. et al., 2021). SIRT6 reduction impairs vascular endothelial function in hyperlipidemic mice, according to in vivo investigations (Jin et al., 2020). Increased SIRT6 activity could be a viable treatment approach for atherosclerotic disease as it is essential for preserving endothelial function (Xu et al., 2016). SIRT6 on EndMT in mice and human HUVECs revealed that co-treatment with TNF-α and IL-1β promotes EndMT and reduces SIRT6 expression (Vijakumaran et al., 2023).

Adenovirus-mediated overexpression of SIRT6 inhibits inflammation-induced EndMT, but SIRT6 knockdown enables it and suppresses EndMT by reducing the inflammatory response of vascular endothelial cells (Chen et al., 2021). Moreover, it has been demonstrated that SIRT6 overexpression significantly augmented autophagic flux in macrophages, inhibited apoptosis, and lowered the expression of VCAM-1, ICAM-1, and P-selectin. This in turn reduced macrophage and foam cell infiltration and suggests a novel therapeutic strategy for enhancing atherosclerotic plaque stability (Wang et al., 2020). SIRT6 inhibits the synthesis and activation of NAD(P)H oxidase, which controls vasomotor function in conduit arteries. In animals lacking the SIRT6 haplotype, NAD(P)H oxidase improves endothelial function, activation, and/or histone acetyltransferase inhibition (Greiten et al., 2021). SIRT6 plays a key negative regulator of atherosclerosis progression and endothelial dysfunction (Liu Z. et al., 2016), and the suppression of SIRT6 in vascular smooth muscle cells may lead to vascular calcification via impairing DNA damage repair processes (Wang et al., 2022).

Moreover, it is believed that the SIRT7 mutant mice’s cardiac condition is partially caused by increased p53 activation due to a lack of SIRT7-mediated deacetylation (Vakhrusheva et al., 2008). It was shown that mice receiving high doses of vitamin D had hardened arteries with reduced SIRT7 expression. The SIRT7/KLF4 axis modulates pulmonary artery endothelial cell homeostasis by influencing proliferation, migration, and tube formation. PAEC dysfunction may be ameliorated either through NAD⁺ supplementation or overexpression of SIRT7 driven by an adeno-associated virus type 1 vector, leading to favorable pulmonary hypertension phenotypes (Zhang et al., 2024b). Apoptotic processes and mitochondrial dysfunction in human aortic endothelial cells (teloHAECs) exposed to IL-6 were examined in relation to miR-148a-3p. The expression of miR-148a-3p reduces during IL6-activated inflammatory pathways, opposing cytokine production and apoptotic cell death and, in turn, enhancing mitochondrial redox homeostasis and respiration (Anastasio et al., 2024).