The transcription factor FoxO belongs to the forkhead protein O family, being one of the important transcription factors in the human body. It regulates the expression of genes that modulate glucose and lipid metabolism, oxidative stress, apoptosis, autophagy, and endoplasmic reticulum stress (Xing et al., 2018). It plays a key role in the development of cardiac remodeling (Zhang et al., 2021a). The effect of SIRT1 on FoxO function is complex and depends on FOXO target genes (Karbasforooshan and Karimi, 2017). Treatment with Ang II increased the acetylation of FoxO1 in vivo and in vitro, and subsequently the pro-apoptotic protein Bim was upregulated. Sirt1 overexpression deacetylated FoxO1, inhibiting Ang II-induced FoxO1 acetylation and reducing the level of the pro-apoptotic protein Bim. However, these beneficial effects were not observed after SIRT1 knockdown (Li et al., 2019b). Diabetic cardiomyopathy (DCM) is one of the main causes of myocardial remodeling. Notably, SIRT1-FoxO1 pathway was significantly inhibited in DCM mice, accompanied by increased myocardial apoptosis. So, Inhibition of SIRT1-FoxO1 pathway may be an important mechanism mediating diabetic induced cardiomyopathy. To prevent ambiguity, we have changed the description. Curcumin, a natural polyphenol isolated from turmeric root, has antioxidant, anti-inflammatory, anti-apoptotic, and anti-cancer effects. Curcumin partially restores SIRT1-FoxO1 pathway activity and inhibits apoptosis both in vitro and in vivo. Furthermore, the effect of curcumin on improving apoptosis disappeared after using EX527, a Sirt1 inhibitor (Ren et al., 2020). In addition, Sirt1 reduces p53 expression and apoptosis by targeting the FoxO3 transcription factor, and it deacetylates the DNA repair protein Ku70, which binds to and inactivates the pro-apoptotic factor Bax (Vahtola et al., 2008).

Overexpression of protein p53 owing to mutations of the tumor suppressor gene p53 leads to rapid loss of cell viability, which is characteristic of apoptosis. Increased levels of tumor suppressor p53 are associated with left ventricular hypertrophy and remodeling (Veeroju et al., 2020). MicroRNAs (miRNAs) are highly conserved, non-coding, single-stranded RNAs in eukaryotes. They can specifically recognize and complementarily bind to target mRNAs, leading to the post-transcriptional degradation of target genes (Henning, 2021). Downregulation of miR-128 in mice with heart failure significantly improved myocardial remodeling and counteracted Ang II-induced apoptosis, by targeting the SIRT1/p53 signaling pathway. Conversely, treatment with EX527 abolished the beneficial effect of miR-128 downregulation (Zhan et al., 2021). Taurine, a free intracellular β-amino acid, has cardioprotective effects. In mice with aortic constriction (TAC)-induced cardiomyocyte hypertrophy, compared to control, taurine significantly decreased the levels of acetylated (at Lys382) p53/p53. Taurine increased the NAD⁺/NADH ratio, promoted SIRT1 expression, inactivated p53 deacetylation, and inhibited cardiomyocyte apoptosis. Furthermore, EX527 mitigated the beneficial effects of taurine on cardiac function, levels of natriuretic peptide, and apoptosis (Liu et al., 2020). Anthracycline chemotherapeutic agents, such as doxorubicin (DOX), cause cardiotoxicity. DOX treatment leads to apoptosis through p53 activation. Thus, by regulating the levels of p53 expression, SIRT1 activation significantly reduces DOX-induced fibrosis, hypertrophy, and apoptosis in H9c2 cardiomyocytes (Lohanathan et al., 2022). CTRP3 preserves DOX-induced cardiac dysfunction and alleviates DOX-induced cardiac inflammation and apoptosis by activating SIRT1, So, sirt1 is an important therapeutic target for correcting DOX induced cardiac remodeling (Yuan et al., 2018).

AMPK is considered cellular fuel. Cellular energy is a key regulator of the AMPK system (Carling, 2017). The cellular energy imbalance that occurs during stress leads to an increase in the intracellular AMP/ATP ratio, resulting in AMPK activation. This helps cells survive without oxygen (Horman et al., 2012). In myocardial tissue, under pathological conditions, such as hyperglycemia, hypoxia, and pressure overload, AMPK activation is significantly downregulated (Li et al., 2019a; Zhang et al., 2020). In diabetic rats, treatment with metformin and atorvastatin reduced the levels of expression of caspase-3 and increased the Bcl-2/Bax ratio. Furthermore, in diabetic rats, the levels of expression of p-AMPK and Sirt1 were downregulated, and this was reversed by the combination treatment, which subsequently increased NAD⁺ levels and reduced apoptosis in cardiomyocytes (Jia et al., 2021; Laddha and Kulkarni, 2021). It's worth noting that AMPK is a trimeric serine/threonine protein kinase comprising a catalytic α subunit and non-catalytic β and γ subunits, which are encoded by seven different high-homologous genes (α1, α2, β1, β2, γ1, γ2, γ3). However, in the existing literature, the differences in the regulation of SIRT1 by AMPA coding from different high-homologous genes have not been clarified.

In an angiotensin-induced hypertension model, SIRT1 overexpression attenuated Ang II-induced ROS formation. Sirt1-mediated deacetylation of FoxO1 directly controlled the expression of catalase and MnSOD, thereby promoting the breakdown of ROS and suppressing oxidative stress (Li et al., 2019b). In H9C2 cells, Ang II increased the concentration of malondialdehyde and decreased SOD activity, thus inducing oxidative stress. Furthermore, it reduced the levels of expression of SIRT1 and FoxO1. Conversely, addition of a SIRT1 agonist attenuated the Ang II-induced oxidative stress index (Jiang et al., 2021). Fibroblast growth factor 20 (FGF20) is a member of the fibroblast growth factor family and is involved in apoptosis, senescence, inflammation, and autophagy. FGF20 upregulates SIRT1 expression, leading to FOXO1 deacetylation, which promotes the transcription of downstream antioxidant genes, thereby suppressing oxidative stress. It has anti-hypertrophic effect which is greatly counteracted in SIRT1 knockout mice. Furthermore, these mice also presented an increase in oxidative stress (Chen et al., 2022b).

NF-κB, a classical signaling pathway, is involved in the development of myocardial remodeling, and inhibition of its phosphorylation can help treat myocardial hypertrophy (Yu et al., 2013). A major component of ginseng, ginsenoside Rg3, has anti-aging effects [27] and ameliorates Ang-II-induced myocardial remodeling. The underlying mechanism consists of the regulation of the Sirt1/NF-κB pathway leading to downregulation of the expression of superoxide dismutase, malondialdehyde, heme oxygenase-1 (HO-1), and nuclear factor (erythroid-derived 2)-like2 (Nrf2). This reduction of oxidative stress ameliorates myocardial remodeling, and the phenomenon is counteracted by the administration of Sirt1 inhibitor AGK2 (Ren et al., 2021).

In an animal model of DCM, Sirt1 decreased the activity of TGF-β and prevented myocardial remodeling by inhibiting p300. Sirt1 deacetylates p65 subunit of NF-kB, leading to reduced binding of NF-KB-P65 to DNA. Subsequently, this reduces cardiac hypertrophy and oxidative stress by diminishing the transcription of subunits of NADPH oxidase (NOX1 and NOX2) (Karbasforooshan and Karimi, 2017). Epithelial mesenchymal transition (EndMT) is closely associated with pathogenesis of myocardial remodeling. EndMT is strongly induced by TGF-β. SIRT1 pathway inhibits EndMT by inhibiting the TGFβ/Smad pathway, thereby reducing cardiac fibrosis and reversing myocardial remodeling (Liu et al., 2019). Thus, ellagic acid, a phytochemical found mainly in nuts and some fruits (e.g., raspberries, grapes, and pomegranates), activated SIRT1 and inhibited TGF-β, suppressing oxidative stress and inhibiting myocardial remodeling caused by DCM (Altamimi et al., 2020). TGF-β promotes the development of fibrotic disease by enhancing collagen expression and inducing cell differentiation into myofibroblasts. And SIRT1 binding to Smad2/3 inhibited Smad2/3 nuclear translocation, thereby regulating myocardial remodeling via the TGF-β/Smad2/3 pathway in cardiac fibroblasts (Liu et al., 2019).

Mitochondrial biogenesis is a central player in the pathophysiology of many cardiovascular diseases, including myocardial remodeling (Forte et al., 2021). Oxidative stress is closely associated with mitochondrial biogenesis. One major regulator of this phenomenon is PGC-1α which is activated by Sirt1 through deacetylation. Subsequently, mitochondrial function improves and ROS production is reduced (Waldman et al., 2018). Neuraminidase-1 (NEU1) is involved in the response to multiple signals and regulates a variety of cellular metabolic processes. Furthermore, it is closely associated with the onset and progression of cardiovascular disease. NEU1 knockdown attenuates cardiomyocyte injury by regulating the SIRT1/PGC-1α signaling pathway, thereby promoting mitochondrial biogenesis and function. Canagliflozin is used to treat type 2 diabetes and improves myocardial remodeling, and therefore being recommended in heart failure guidelines. This effect is mediated by the activation of the AMPK/SIRT1/PGC-1α signaling pathway, upregulating PGC-1α expression and reducing cardiac hypertrophy, fibrosis, and oxidative stress (He et al., 2022a).

Additionally, the levels of expression of SIRT1 are modulated by AMPK, which thus, is implicated in the control of ROS levels. During the development of cardiac remodeling, energy deficits can exacerbate cardiac insufficiency. Elevated expression of antioxidants (SOD1, catalase, and MnSOD) and reduced mitochondrial ROS production mitigates myocardial remodeling. AMPK is an upstream regulator of Sirt1. As mentioned before, in reality, AMPK and Sirt1 regulate each other and share many common target molecules; AMPK increases NAD⁺ levels and activates Sirt1 (Wang et al., 2020b). The expression levels of p-AMPK and SIRT1 were reduced in diabetic mice and in H9C2 cells exposed to high concentrations of glucose. Combined treatment with metformin and atorvastatin activated the AMPK/SIRT1 signaling pathway, thereby attenuating cardiomyocyte fibrosis, hypertrophy, and oxidative stress (Jia et al., 2021). Aldehyde dehydrogenase 2 (ALDH2) is an essential mitochondrial enzyme that controls cardiac function. It exacerbates aging-induced cardiac hypertrophy, oxidative stress, and mitochondrial damage. AMPK/SIRT1 activation (resveratrol and SRT1720) prevented ALDH2-induced contractile dysfunction in cardiomyocytes. AMPK enhances SIRT1 activity by increasing cellular NAD⁺ levels, leading to deacetylation and regulation of the activity of downstream targets of SIRT1, including PGC1α, thereby reducing oxidative stress in cardiomyocytes (Zhang et al., 2014).

In summary, the main molecular mechanism of SIRT1-mediated regulation of oxidative stress is the modulation of the levels of expression of catalase and MnSOD through SIRT1-mediated FoxO1 deacetylation, which leads to the inhibition of the production of ROS and suppression of oxidative stress. PGC-1α and NF-κB are activated by SIRT1 through deacetylation, thereby improving mitochondrial function and counteracting the pro-oxidant effect of cell stress, thereby reversing cardiomyocyte remodeling.

Among drugs that prevent myocardial remodeling, angiotensin-converting enzyme inhibitors (ACEIs) are commonly used in clinical practice. Furthermore, they promote autophagy in cardiomyocytes (Wu et al., 2013) owing to the activation of the AMPK pathway (Hernández et al., 2014). Metformin is an activator of AMPK and is used clinically for the treatment of diabetes. It can reduce the serious complications of diabetes, including myocardial remodeling and heart failure by upregulating SIRT1 and AMPK and subsequently, promoting autophagy (Xie et al., 2011). Sodium-glucose cotransporter (SGLT2) is not expressed in the heart but SGLT2 inhibitors are recommended by the latest treatment guidelines in patients with heart failure, with or without diabetes mellitus. SGLT2 inhibitors may directly bind to SIRT1, thus inhibiting autophagy (Osataphan et al., 2019).

Treatment of rat cardiomyocyte cell lines with Ang II results in insufficient cardiomyocyte autophagy and interferes with the expression of the autophagy-associated proteins beclin1 and p62. Ginkgolide B Protects Cardiomyocytes from Angiotensin II-Induced Hypertrophy via Regulation of Autophagy through SIRT1-FoxO1 (Jiang et al., 2021). Another study showed that SIRT1-dependent deacetylation of the transcription factor Foxo1 is involved in cardiac senescence: SIRT1 activates FoxO1, promoting its nuclear localization, and Akt inhibits it by phosphorylation, preventing nuclear translocation. The inhibition of SIRT1-Foxo1-mediated autophagy in aged mice can be counteracted by the ablation of Akt2, an enzyme that has the opposite effect (Ren et al., 2017).

FGF21 is a novel peptide ligand involved in a variety of physiological and pathological processes, including regulation of glucose and lipid metabolism and reduction of atherosclerotic plaque formation in large blood vessels. It also plays a cardioprotective role in myocardial infarction, cardiac ischemia-reperfusion injury, cardiac hypertrophy, and DCM (Geng et al., 2020). In animal models of DCM, diabetes-induced oxidative damage and inflammation inhibited cardiac autophagy, suggesting that these phenomena contribute to the pathogenesis of diabetic heart disease (Zhang et al., 2016). Fenofibrate (FF), a peroxisome proliferator-activated receptor-α (PPARα) agonist, is used clinically to treat hypertriglyceridemia. In a mouse model of diabetic cardiomyopathy, pre-treatment with FF partially restored autophagy in diabetic hearts. Furthermore, the cardioprotective effect of FF in type 1 diabetes mellitus is dependent on FGF21. The upregulation of cardiac FGF21 expression may increase SIRT1-mediated autophagy, which plays a key role in preventing diabetes-induced cardiac inflammation, oxidative stress, fibrosis, and dysfunction (Zhang et al., 2016). In vitro studies using H9C2 cells also showed that exposure to high glucose (HG) significantly increased inflammatory responses, oxidative stress, and pro-fibrotic responses, and significantly inhibited autophagy. The effects of HG were inhibited by treatment with FF. Inhibition of autophagy by 3-methyladenine (3 MA) or SIRT1 by sirtinol (SI) counteracted the beneficial effects of FF. Thus, FF may prevent cardiac pathology and functional abnormalities caused by type 1 diabetes by increasing FGF21 levels, which may upregulate SIRT1-mediated autophagy. Moreover, FGF21 is involved in multiple disease processes through SIRT1-dependent autophagy, including wound healing (Chen et al., 2022a), osteoarthritis (Lu et al., 2021b), and acute liver injury (Yang et al., 2022), which overlaps with the pathological mechanism of myocardial remodeling So, SIRT1-dependent autophagy mediated by FGF21 may be an important mechanism involved in pathological myocardial remodeling.

In summary, SIRT1-dependent deacetylation of FoxO1 prevents cardiac senescence and enhances cellular autophagy. SIRT1 plays a key role in preventing diabetes-induced cardiac inflammation, oxidative stress, and dysfunction. Ang-II induces cardiac hypertrophy by suppressing SIRT1 expression, whereas ginkgolide B counteracts it by enhancing autophagy through the activation of the SIRT1-FoxO1 pathway.

Since SIRT1 and its regulation play an important role in human diseases, there is an increasing interest in discovering small molecules that modulate its activity. Common agonists of SIRT1 are reviewed here. The polyphenol resveratrol (RSV), a natural compound, was the first SIRT1 agonist. Resveratrol exhibits a wide range of physiological and biochemical activities, including antioxidant, anti-inflammatory, antiplatelet, and anticoagulant activities, suggesting that its administration is beneficial for cardiovascular diseases (Bonnefont-Rousselot, 2016). RSV inhibits cell membrane lipid oxidation, protects low-density lipoprotein from oxidation, and increases the concentration of high-density lipoprotein (Berrougui et al., 2009). RSV has antithrombotic effects and inhibits thrombosis by inhibiting prostaglandin and thromboxane synthesis and platelet activity (Snopek et al., 2018). In the cardiovascular system, disturbances in intracellular calcium homeostasis lead to cardiovascular system dysfunction, including cardiac systolic dysfunction, arrhythmias, remodeling, and apoptosis. RSV differentially regulates Ca²⁺ handling by stimulation of NO production or antioxidant activity, maintaining Ca²⁺ homeostasis under normal and pathological conditions (Liu et al., 2017). Other SIRT1 agonists include small molecules that are structurally different from RSV, but hundreds of times more potent, such as SRT1720 and SRT501.

SIRT1 agonists are considered beneficial in a variety of diseases, as demonstrated in various animal models. However, SIRT1 inhibitors might be beneficial in cancer, Parkinson’s disease, and infection with human immunodeficiency virus (HIV) (Pagans et al., 2005; Alcaín and Villalba, 2009). Sirtinol induces senescence-like growth arrest in human breast cancer MCF-7 and lung cancer H1299 cells (Ota et al., 2006). Sirt1 activation promotes chronic granulocytic leukemia (CML) cell survival, and proliferation is associated with the deacetylation of multiple SIRT1 substrates, including FoxO1, p53, and KU70. Treatment of mice with the SIRT1 inhibitor tenovin-6 prevents cancer progression (Yuan et al., 2012). Table 2 shows both the inducers and inhibitors of SIRT1.

SIRT1 activators have been proposed as a therapeutic strategy for treating and preventing vascular disease. A clinical trial proved that the defective Sirt1 may be correlated to the abnormal IFNγ expression in severe aplastic anemia patients, and activation of Sirt1 signaling by SRT3025 may help improve the inflammatory status of severe aplastic anemia (Lin et al., 2019). And Sowmya found SRT2104, an activator of SIRT1, appears to be safe and well tolerated and associated with an improved lipid profile without demonstrable differences in vascular or platelet function in otherwise healthy cigarette smokers based on a double-blind trial (Venkatasubramanian et al., 2013). At present, more ongoing clinical trials areunderway to investigate the efficacy, pharmacokinetics, and safety of Sirtuin modulator compounds inseveral diseases (http://clinicaltrials.gov). Unfortunately, there are still reports about the use of sirt modulators in clinical trials. So, future research should aim to elucidate the role of Sirt1 completely and to develop pharmacological strategies that can allow its action to be modulated (Table 2).