Inflammation, oxidative stress, autophagy, and cardiomyocyte apoptosis ultimately contribute to cardiac dysfunction in sepsis [8, 9]. Large amounts of reactive oxygen species (ROS) and reactive nitrogen species are accumulated. When the oxidation/antioxidation becomes unbalanced, excessive ROS production can cause damage to the cardiac, as well as damage the structure of cardiomyocytes and promote apoptosis directly [10]. In addition, excessive ROS production during sepsis can exacerbate myocardial inflammation, attenuates the endothelium-dependent vasodilatory response and exacerbates microcirculatory disturbances [11].

During the acute infection stage of sepsis, some monocytes are activated and produce a variety of cytokines such as tumor necrosis factor-$\alpha$ (TNF-$\alpha$) and interleukin-1$\beta$ (IL-1$\beta$). These cytokines trigger an inflammatory cascade, which in turn leads to apoptosis and cytotoxicity of cardiomyocytes and endothelial cells [12]. Sepsis-induced myocardial damage occurs when macrophages infiltrate the heart. Nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3)-mediated inflammatory responses occur in macrophages, releasing multiple pro-inflammatory factors and causing accumulation of ROS in cardiomyocytes, leading to cardiac dysfunction. The NLRP3 inflammasome activates caspase-1, produce IL-18, and IL-1$\beta$, and triggers inflammation and focal death [13, 14]. Recent studies have provided intriguing evidence suggesting that SIRTs may indeed influence NLRP3 activation. These studies have shown that SIRT3, in particular, can deacetylate and inhibit the activity of the nuclear factor kappa-B (NF-$\kappa$B) pathway, a major regulator of NLRP3 gene expression [15, 16]. By suppressing NF-$\kappa$B signaling, SIRT3 may indirectly downregulate NLRP3 inflammasome activation, potentially mitigating the excessive inflammation observed in sepsis.

Several studies have reported that aberrant host responses mediated by Toll-like receptors (TLR) contribute to the pathogenesis of sepsis [17, 18, 19]. TLR is expressed in immune and other cells, including cardiomyocytes, and interacts with different pathogen-associated molecular patterns (PAMPs), leading to activation of NF-$\kappa$B and subsequent formation of pro-inflammatory cytokines [20]. TNF-$\alpha$ is a cause of cardiovascular changes associated with infectious shock, including myocardial dysfunction [21]. TLR7 as pattern recognition receptors were found in the intranuclear soma membrane [22]. The expression of TLR7 is upregulated in cardiomyocytes in response to sepsis, and TLR7 activation further activates the Cyclic Adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway in the sarcoplasmic reticulum [19, 22]. Activated TLR7 narrow moves into the Golgi apparatus and endosomes, and enhances the myeloid differentiation primary response 88 (MyD88)/interleukin-1 receptor associated kinase1 (IRAK)/NF-$\kappa$B cascade, ultimately leading to inflammation [23]. Furthermore, TLR7 regulates Ca${}^{2+}$ release through activation of the adenosine (cAMP)-protein kinase A (PKA)-phospholamban (PLN) pathway and protects against sepsis-induced myocardial damage [19].

Activation of the TLR4 signaling pathway may directly contribute to cardiomyocyte dysfunction. Besides, sepsis directly impairs cardiac function by binding to its receptor TLR4 through its binding protein CD14, which produces inflammatory factors such as TNF-$\alpha$, IL-1$\beta$, and IL-18 [24]. Invasive bacteria or other external stimuli first trigger innate immunity, which then induces TLR4 expression through activation of NF-$\kappa$B transcription, leading to the production of various inflammatory mediators such as cytokines, chemokines, and antimicrobial peptides [25]. Other cell wall components of pathogenic microorganisms (e.g., lipoproteins) are released and recognized by pattern recognition receptors (e.g., 2, 5, 9), leading to inflammation and dysfunction of cardiomyocytes [26, 27]. Sepsis activates Janus Kinase 2 (JAK2)/transcription 6 (STAT6) phosphorylation, which is accompanied by increased levels of oxidative stress, apoptosis and inflammatory responses in cardiomyocytes thereby causing cardiomyocyte damage [12].

MiR-146a is typically considered a negative regulator of the TLR4 and NF-$\kappa$B signaling pathways. It acts to inhibit the expression and activity of TLR4 and NF-$\kappa$B, thus exerting an anti-inflammatory effect [28]. NF-$\kappa$B rapidly translocate from the cytoplasm to the nucleus, initiating transcription of target genes and releasing downstream inflammatory factors, including TNF-$\alpha$ and IL-6. Then TNF-$\alpha$ and IL-6 contribute to the myocardial dysfunction observed in sepsis by inhibiting Ca${}^{2+}$ transport, regulating nitric oxide pathways, degrading key contractile proteins, affecting mitochondrial function, and activating intracellular signaling to inhibit the myocardium [29, 30, 31, 32, 33].

Sepsis triggers endoplasmic reticulum stress, leading to activation of calmodulin-dependent protein kinase kinase beta (CaMKK$\beta$) and adenosine 5${}^{\prime }$-monophosphate-activated protein kinase (AMPK), inhibiting the mTOR signaling pathway and ultimately leading to excessive autophagy. Meanwhile, sepsis promoted early endosome formation to favor autophagosome formation, while inhibiting late endosome formation to delay autophagic lysosome formation [34].

Mitochondria, as energy suppliers to cardiomyocytes, contribute to the pathophysiology of myocardial dysfunction in sepsis [35]. Mitochondrial dysfunction associated with septic cardiomyopathy consists of the following: changes in mitochondrial structure (swelling, internal vesicle formation, and cristae abnormalities), mitochondrial DNA damage, elevated mitochondrial permeability transition, and inhibition of cytochrome C oxidase activity [36, 37, 38, 39]. Sepsis causes mitochondrial damage through multiple mechanisms [40, 41]. Damaged mitochondria promote cardiomyocyte apoptosis, which in turn exacerbates sepsis-induced myocardial damage. Biogenesis of damaged or defective mitochondria is associated with accumulation of useless or dysfunctional mitochondria with reduced mitochondrial potential or increased ROS [42]. These damaged mitochondria subsequently interfere with cardiomyocyte metabolism and induce mitochondrial apoptosis or necrosis via activation of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (mPTP) [43, 44].

Mitochondrial damage and dysfunction are highly associated with sepsis-induced myocardial damage [45, 46]. Mitochondria are the main source of intracellular ROS in the myocardium during sepsis. Sepsis damages myocardial mitochondria by disrupting membrane integrity, which in turn increases ROS production and oxidative stress [47]. Increased ROS production leads to oxidative stress that impairs mitochondrial biosynthesis, division/fusion homeostasis, and mitochondrial autophagy, thereby promoting apoptosis, hypertrophy, and remodeling, which have been widely reported in sepsis-induced cardiac, renal, and pulmonary damage [48]. The expression of Gasdermin D (GSDMD) functional fragment is up-regulated in the heart tissue of septic WT mice, accompanied by reduced cardiac function and myocardial injury. GSDMD leads to mitochondrial dysfunction and ROS overproduction by enriching mitochondria, which in turn regulates the activation of NLRP3 inflammasome, leading to myocardial injury, pyroptosis, and cell death in sepsis. GSDMD enrichment in the mitochondrial membrane triggers ROS production and may be partially involved in NLRP3 activation [49, 50]. NLPR3-deficient mice show improved cardiac systolic and diastolic function and increased survival from sepsis [51]. GSDMD plays a role in sepsis plays an important role in the pathophysiology of sepsis-induced myocardial damage [50].

In addition, inhibition of the NLRP3/IL-1$\beta$ axis prevents systolic and diastolic dysfunction in sepsis [51]. Because IL-1$\beta$ activates NF-$\kappa$B through its receptor, this leads to decrease deformability, and decreased cardiomyocyte contraction and diastole. In turn, it leads to septic cardiomyopathy with myocardial atrophy, cardiac systolic and diastolic dysfunction and increased expression of pro-inflammatory cytokines of the cardiac [51]. Overall, inhibitors of NLRP3 inflammasomes, IL-1$\beta$, interleukin- 1 receptor antagonist (IL-1RA), and NF-$\kappa$B are used to prevent sepsis-induced myocardial damage.

We summarized the current mechanism of myocardial damage caused by sepsis, and then we started from the damage mechanism to explore whether SIRTs can inhibit these damages and thus achieve protective effects. The molecular mechanisms of mitochondria associated with myocardial damage caused by sepsis are summarized in Fig. 1.

Fig. 1.

Schematic representation of the pathogenesis of sepsis-induced myocardial damage. Sepsis triggers a complex cascade of reactions, including the activation of oxidative stress, the occurrence of autophagy, apoptosis and systemic inflammatory response. IL, interleukin; AMPK, adenosine 5${}^{\prime }$-monophosphate-activated protein kinase; ROS, reactive oxygen species; NLRP3, Nucleotide-binding and oligomerization domainlike receptor protein 3; TLR, Toll-like receptors; TNF-$\alpha$, tumor necrosis factor-$\alpha$; PLN, phospholamban; PKA, protein kinase A; cAMP, Cyclic Adenosine monophosphate; IRF3-p, Type-I interferons regulatory factor 3- Phosphorylated; Trx, thioredoxin; TXNIP, Thioredoxin-interacting protein; mTOR, mammalian target of rapamycin; ASC, apoptosis-associated speckle-like protein; RAB, Ras-related proteins in brain; GYY4137, hydrogen sulfide donor.

SIRT1 is a conserved NAD${}^{+}$-dependent protein deacetylase that exerts anti-inflammatory, antioxidant, and anti-aging effects by regulating gene transcription, chromosome stability, and target protein activity through deacetylation [52], which is reported to be involved in sepsis-induced myocardial damage.

Clinical studies have found that SIRT1 can still be clinically relevant as a rapid measurable prognostic biomarker for patients with sepsis in the clinical setting [53]. SIRT1 expression is downregulated in the hyper-inflammatory response to sepsis, and SIRT1 activation counteracts sepsis-induced myocardial damage [54, 55, 56]. Besides, SIRT1 played a negative role in regulating the activation of NLRP3 inflammasome [57, 58]. NLRP3 interacts with apoptosis-associated speckle-like protein (ASC) and promotes its own cleavage and activation through ASC recruitment of caspase1 precursor monomers. Thus, activated caspase 1 stimulates the cleavage of pro-IL-1$\beta$ and pro-IL-18 into mature IL-1$\beta$ and IL-18, which triggers an inflammatory response [59, 60]. Resveratrol (RESV), plant antioxidant, has been shown to reduce myocardial damage in sepsis by activating SIRT1 signaling to reduce neutrophil accumulation, TNF-$\alpha$ expression, and cardiomyocyte apoptosis [61]. In studies of acute renal damage caused by sepsis, SIRT1 mitigates acute renal damage by promoting autophagy mediated by deacetylation of Beclin1. However, this mechanism has not been validated in the cardiac and therefore needs to be further explored [7].

Besides, injection of a cell-permeable Tat-Beclin-1 peptide to activate autophagy improved cardiac function, attenuated inflammation, and rescued the phenotypes caused by Beclin-1 deficiency in sepsis-challenged mice, this suggests that Beclin-1 protects against cardiac damage during sepsis [62]. miR-181a is one of the MicroRNAs that represses gene expression at the post-transcriptional level by binding to target mRNAs [63]. MiR-181 levels were significantly increased in the presence of enhanced inflammatory response and apoptosis. MiR-181 binds directly to its target genes and inhibits SIRT1 expression. MiR-181a inhibition leads to upregulation of SIRT1 expression and downregulation of pro-inflammatory cytokines and apoptosis. Inhibition of miR-181a attenuates sepsis-induced inflammation and apoptosis by activating the Nuclear factor erythroid2-related factor 2 (Nrf2) pathway while inhibiting the NF-$\kappa$B pathway, achieved through the targeting of SIRT1 [63]. Thus, miR-181 plays a key role in inflammation during sepsis and could be a potential therapeutic target for patients with sepsis. Serum lactate has been recognized as a biomarker of sepsis prognosis, and elevated serum lactate levels are positively correlated with sepsis mortality [64]. Clinical studies have shown that circulating high mobility group box-1 (HMGB1) levels are significantly elevated and positively correlate with the severity of sepsis and mortality [65, 66]. Lactate can strongly inhibit the gene expression of SIRT1 [67]. SIRT1 acetylation promotes HMGB1 release and is essential for sepsis pathogenesis [68]. This process is closely linked to the pathogenic role of lactate in sepsis, as lactate can inhibit SIRT1’s nuclear translocation and its function in deacetylation [7].

Restoring mitochondrial quality control mechanisms by activating mitochondrial biosynthesis or reducing mitochondrial division is a promising approach to improve organ dysfunction in sepsis [69, 70]. SIRT1/peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1$\alpha$) network enhances the regulation of cardiac mitochondrial activity and plays a protective role in sepsis-induced myocardial injury [71, 72]. Melatonin upregulates SIRT1 and autophagy, protecting from sepsis in relation to mitochondrial mechanism [73].

SIRT2, far less studied than SIRT1, is mainly located in the cytoplasm, but under certain conditions, it also enters the nucleus and performs the corresponding functions [74]. SIRT2 is a nutrient sensor in adipose and immune cells, like SIRT1, increased caloric restriction lead to a high nutrient and high fat diet decreases SIRT2 expression in white adipose tissue of mice [75, 76]. In obese mice with sepsis, elevated levels of SIRT2 protein instead prolonged low inflammation; SIRT2 is the most abundant SIRTs in adipose tissue [77]. Specifically, there are some studies found that through direct deacetylation of NF-$\kappa$B and p65. SIRT2 expression in obesity with sepsis was reduced in the high inflammatory phase and increased in the low inflammatory phase [78].

SIRT3 is an NAD${}^{+}$-dependent histone deacetylase with functions in the regulation of mitochondrial oxidative stress, bioenergetics, anti-senescence, anti-fibrosis, and anti-inflammation [79, 80, 81, 82]. In the cardiac, SIRT3 is highly expressed and is required for the maintenance of cardiomyocyte energy and cardiac contractility [83]. SIRT3 located mainly in mitochondria, represents the major protein deacetylase in mitochondria and detoxifies ROS and increases mitochondrial ATP regeneration by activating manganese superoxide dismutase (MnSOD) and various energy metabolizing enzymes [83, 84, 85, 86]. The activation of SIRT3 is currently considered as a potential therapeutic strategy for the treatment of septic cardiomyopathy [87]. It was demonstrated that SIRT3 expression was significantly reduced in myocardial tissue from mice with sepsis-induced cardiac damage, and that restoration of SIRT3 expression prevented sepsis-induced cardiac damage [88]. Antioxidant and anti-inflammatory effects on the SIRT3 have also been demonstrated in sepsis-induced cardiac damage [89].

Mitochondrial dysfunction impairs the contractility of cardiomyocytes and even triggers cardiomyocyte death [90]. Annexin A1 (ANXA1), a glucocorticoid-regulated protein that is widely expressed in human tissues and cells [91]. ANXA1 promotes p53 deacetylation in sepsis-treated H9C2 cells by enhancing SIRT3 expression thereby reducing cardiomyocyte death [92]. Impaired SIRT3 activity may mediate cardiac dysfunction in endotoxemia by promoting calpain-mediated disruption of ATP synthesis, suggesting SIRT3 activation as a potential therapeutic strategy for the treatment of septic cardiomyopathy [87]. Tubeimoside I (TBM) prevents sepsis-induced endothelial dysfunction by reducing oxidative stress and apoptosis through SIRT3. TBM is a promising new therapeutic agent for sepsis-induced endothelial dysfunction [89]. Polydatin-mediated SIRT3 activation preserves mitochondrial function through mitochondrial superoxide dismutase 2 (SOD2) and Cyclophilin D (CypD) deacetylation, thereby reversing sepsis-induced endothelial hyperpermeability [93]. In addition, the role of SIRT3-CypD signaling in barrier protection was identified. SIRT 3-mediated deacetylation inhibited CypD activity, thereby inhibiting mPTP opening and $\mathrm{\Delta }$$\mathrm{\Psi }$m reduction [94]. It was shown that reduced CypD hyperacetylation and interaction with SIRT3 in response to sepsis attack resulted in a reduction in mPTP opening and subsequent $\mathrm{\Delta }$$\mathrm{\Psi }$m [93]. Estrogen related receptors (ERRs) can bind to the SIRT3 promoter and induce transcription of SIRT3 [95]. Tubeimoside I may protect against sepsisinduced cardiac dysfunction (SICD) by binding to and activating ERR$\alpha$, thereby activating ERR$\alpha$ to promote SIRT3 transcription to reduce inflammation, oxidative stress and apoptosis [89].

SIRT3 deficiency leads to hyperacetylation of key enzymes in the cardiac trichloroacetic acid (TCA) cycle, which subsequently shifts myocardial metabolism to anaerobic glycolysis and subsequently promotes lactate and nicotinamide adenine dinucleotide (NADH) production, ultimately exacerbating cardiac function after sepsis [88]. SIRT3 overexpression increases AMPK activity and improves mitochondrial biosynthesis, which maintains mitochondrial function and reduces sepsis-associated cardiomyocyte damage [90]. These studies suggest that targeting SIRT3 may provide a potential new target to maintain normal cardiac performance after sepsis. However, the precise mechanisms of protection still need further investigation.

Unlike SIRT1 and SIRT3 deacetylases, SIRT5 has relatively weak deacetylation, but shows stronger desuccinylation activity, mainly removing succinyl, malonyl and glutaryl groups from lysine residues of mitochondria and peroxisome metabolic enzymes [96]. For example, SIRT5 has been reported to be able to descuccinylate pyruvate dehydrogenase 1 (PDHA1) and succinate dehydrogenase (SHDB), and play a role in regulating the activity of these protein [97]. As a member of SIRTs, SIRT5 has been proved to be located in mitochondria and cytosol [98]. As far as its cell biological function is concerned, SIRT5 can promote ammonia detoxification, regulate glycolysis, TCA cycle and electron transfer chain. In addition, SIRT5 can also promote fatty acid $\beta$ oxidation and ketone body production [99]. Studies have shown that SIRT5 deficiency can promote enteritis, acute lung damage and ischemia-reperfusion damage [96].

In sepsis, SIRT5 has also attracted great attention. Studies have shown that in sepsis, SIRT5 can enhance the innate inflammatory response of macrophages or endotoxin-tolerant macrophages by promoting the acetylation of p65 and activating NF-$\kappa$B pathway. This process is completed by competing with SIRT2 and blocking the deacetylation of SIRT 2 to p65 [100]. In an experimental study on burn sepsis model in mice, the inhibition of SIRT5 expression reduced the deacetylation of PDHA1, restored the activity of pyruvate dehydrogenase, promoted the polarization of macrophage M2, and alleviated burn sepsis in mice [101]. Another study using renal tubular cells (RTSCs) showed that in sepsis, the expression level of phosphorylation-AMPK (p-AMPK) decreased, the structure of mitochondria was destroyed, and the content of ATP decreased, while AMPK agonists could alleviate septic acute renal damage (SAKI), and this process was mediated by SIRT5. Knockout of SIRT5 will significantly aggravate SAKI. On the contrary, up-regulation of SIRT5 expression can reduce mitochondrial dysfunction of renal tubular epithelial cells (RTECs) and reduce SAKI by enhancing AMPK phosphorylation [102]. In a word, SIRT5 may play a regulatory role in the pathogenesis of sepsis by regulating cell metabolism, apoptosis and oxidative stress.

SIRT6 is another protein that depends on NAD${}^{+}$ for its deacetylation activity. It regulates gene expression by removing acetyl groups from histones and transcription factors. Its biological functions include deacetylation, defatty-acylation, and ADP-ribosylation, which are involved in DNA repair, gene expression, and telomere maintenance, ultimately regulating lifespan and controlling aging [103]. In addition, SIRT6 is also related to energy metabolism, aging, obesity, inflammation, cancer and so on [104].

As far as sepsis is concerned, SIRT6 can reduce the inflammatory reaction of human venous endothelial cells (HUVECs) induced by sepsis by positively regulating the expression of Nrf2 and activating anti-inflammatory and antioxidant enzymes regulated by Nrf2, which suggests that SIRT6 is a possible target for preventing lung damage induced by sepsis [105]. Further research shows that the overexpression of SIRT6 in renal proximal convoluted tubule epithelial cells will alleviate SAKI by activating autophagy, which promotes AMPK activation, inhibits mTOR signaling pathway, promotes the polarization of macrophage M2 in autophagy-dependent and non-autophagy-dependent ways, and then plays a role in alleviating SAKI [104]. In another experiment of damage and apoptosis of renal tubular epithelial cells induced by sepsis, it was found that SIRT6 can activate nuclear factor erythroid-2-related factor 2-antioxidant response element (Nrf2)/ARE signal, alleviate renal dysfunction induced by sepsis, and reduce apoptosis and oxidative stress of renal tubular epithelial cells [106].

Because SIRT6 can promote autophagy, studies show that the overexpression of SIRT6 can alleviate sepsis-induced apoptosis, and further induce autophagy to play a protective role in renal epithelial cell damage caused by sepsis [107]. On the one hand, the up-regulated expression of SIRT6 can promote autophagy, on the other hand, it can protect renal tubular epithelial cells from oxidative stress, inflammatory reaction and apoptosis, and then play a protective role in sepsis-induced renal damage [108]. Another study on the treatment of sepsis shows that the activation of SIRT6 can inhibit the apoptosis of myocardial cells and the expression of inflammatory factors by promoting autophagy, and then inhibit the myocardial dysfunction induced by sepsis [109]. Besides promoting autophagy, SIRT6 plays an important role in regulating glucose metabolism in vivo, and the decrease of SIRT6 activity will reverse glycolysis block related to monocytes caused by endotoxin, which is a process that leads to immune metabolism paralysis of monocytes in human and mice sepsis [110]. This shows that SIRT6 mainly promotes autophagy, reduces oxidative stress and alleviates sepsis mediated by inflammatory factors.

SIRT7 is also a deacetylase belonging to SIRT family. Many studies have shown that SIRT7 can regulate protein deposition, endoplasmic reticulum stress, mitochondrial protein folding and mitochondrial metabolism [111]. SIRT7 is mainly located in nucleoli [112], which combines with ribosomal RNA gene and participates in the transcription process of ribosomal DNA during mitosis. One of its important functions is to regulate chromatin remodeling [113]. SIRT7 can exert deacetylation activity at DNA damage sites, and show other catalytic activities for protein involved in DNA damage and repair [111, 112]. Although there are few studies on the role of SIRT7 in sepsis at present, a study on the mechanism of resveratrol found that the activation of SIRT7 can reduce inflammatory factors and play a positive role in the treatment and protection of sepsis and its cardiac damage [114]. Another study shows that liver damage will be caused during the pathogenesis of sepsis, and the activation of endoplasmic reticulum stress (ERS) pathway will cause apoptosis of hepatocytes. SIRT7 can inhibit glucose-r\regulated protein 78 (GRP78) in ERS pathway to inhibit apoptosis of hepatocytes, which provides clues for the treatment of liver damage caused by sepsis in the future [115]. Due to its unique biological function, SIRTs reduces sepsis by deacetylating several histone and non-histone proteins. Fig. 2 summarizes the role of these SIRTs in cells and their mechanisms of action in sepsis.

Fig. 2.

Schematic representation of SIRTs modulates the inhibition of sepsis through intracellular mechanisms. SIRTs is dispersed in subcellular compartments of cells. Each SIRTs has its own unique targets that define its biological activity, as described in the review. SIRT, Sirtuin; NF-$\kappa$B, nuclear factor kappa-B; GSDMD, Gasdermin D; Nrf2, Nuclear factor erythroid2-related factor 2; SOD2, superoxide dismutase 2; mPTP, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; CypD, Cyclophilin D; ac, acetylation; M2, Macrophages 2; MiR-181a, miRNAs-181a; p65, reLA.