Revealing Landscape of Competing Endogenous RNA Networks in Sepsis-Induced Cardiovascular Diseases

Cardiovascular dysfunction induced by sepsis is one of the most common phenotypes of cardiovascular diseases (CVDs), which is closely related to the high mortality of sepsis and is an urgent health problem to be solved worldwide. Unfortunately, the exact pathogenesis and pathophysiology of sepsis-induced cardiovascular dysfunction are not clear. As a research hotspot in recent years, competing endogenous RNA (ceRNA) networks are involved in the modulation of the pathophysiological progression of many diseases, including sepsis-related CVDs. Both long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) can specifically bind to microRNAs (miRNAs) as ceRNAs to target messenger RNAs (mRNAs), forming a ceRNA network composed of lncRNA/circRNA-miRNA-mRNA. This review demonstrates the potential regulatory mechanism of the ceRNA networks in sepsis-induced cardiovascular toxicity, hoping to provide novel therapeutic strategies and monitoring targets for sepsis-related CVDs.


Introduction
Sepsis is a syndrome of th systemic inflammatory response caused by infection and, ultimately, multiorgan dysfunction [1], which endangers millions of patients worldwide each year and has high mortality rates ranging from one-in-six to one-in-three [2].The cardiovascular system has been considered as the most frequently affected organ system during sepsis and plays a crucial role in the pathophysiology of septic organ dysfunction.Cardiac depression caused by sepsis is a common phenotype in septic cardiomyopathy and suggests a poor clinical prognosis.Septic cardiomyopathy is characterized by reversible systolic and diastolic dysfunction of the heart throughout the cardiac cycle under septic conditions, which involves complex responses to pathogens, excessive inflammation, oxidative response, metabolic energy impairment, endoplasmic reticulum (ER) stress, myocardial apoptosis and structural changes [3], as shown in Fig. 1.In addition, vascular dysfunction has been recognized as the other common phenotype in sepsis, and is associated with glycocalyx damage, endothelial injury, and vascular dystonia, leading to vascular paralysis, microcirculation disturbances, and septic shock [4].Septic shock is usually characterized by fluid resuscitation-refractory hypotension and hyperlactatemia.With the development of training, monitoring and treatment in intensive care units, the hospital mortality of septic shock has dropped from 80% to 30%, but this condition is still lifethreatening [5].
Sepsis-induced cardiovascular diseases (SCVDs, a classic form of CVD) have been confirmed to be the major reason for the increased mortality in patients with sepsis and septic shock, which are considered serious healthcare problems [6].Despite significant advances in anti-infection and organ supportive therapy, sepsis-associated death remains high.Even survivors who suffer from severe sepsis are often left with long-term sequelae and higher recurrence rates, resulting in a huge social, economic and public health burden [7].A great number of studies on septic cardiovascular dysfunction have been carried out in recent decades, but the exact pathophysiology and pathogenesis are still unclear.Sepsis lacks ideal biomarkers and has no specific treatment beyond infection control and symptomatic support [8].Early diagnosis and bundled treatment of sepsis within the first few hours can improve long-term outcomes in SCVDs [9].Therefore, biomarkers for early detection and precision therapy are urgently needed to improve the survival rate and living quality of patients with SCVDs.Elucidating the molecular mechanism of cardiovascular dysfunction induced by sepsis can provide novel monitoring and therapeutic targets for SCVDs.iological processes (such as SCVDs) via ceRNA networks [11].NcRNAs include long non-coding RNAs (lncRNAs, lncRs), circular RNAs (circRNAs, circRs) and microR-NAs (miRNAs, miRs).LncRNAs regulate transcription by splicing and degrading RNA, while posttranscriptional regulation is controlled by decoy and sponge proteins, as well as nuclear compartmentalization and epigenetic modification [12].Different from linear RNA, circRNA consists of a covalently closed loop, which has neither a poly-A tail nor 5 ′ -3 ′ polarity.CircRNAs regulate transcription and translation by binding to miRNAs and interacting with RNAbinding proteins [13].A novel type of epigenetic regulation known as ceRNA is considered to be a natural bait for miRNAs.CeRNA competes the miRNA response element (MRE) to modulate the expression of target messenger RNA (mRNA) [14].Both lncRNAs and circRNAs can serve as ceRNAs that bind with miRNAs to regulate the translation of targeted mRNAs [15], which forms the lncRNA/circRNA-miRNA-mRNA axis that constitutes the basic network of ceRNAs, as shown in Fig. 2. Complex ceRNA networks play important roles in the pathogenesis of SCVDs by regulating apoptosis, immunity, endothelial dysfunction, and inflammation.Notwithstanding, the underlying mechanism of septic CVDs is not yet clear.
Increasing evidence has shown that ncRNAs are specifically expressed in some tissues and developmental stages and can be used as biomarkers for disease diagnosis and prognosis and as potential therapeutic targets [16].The lncRNA/circRNA-miRNA-mRNA axis acts as a sophisticated interactive network that regulates cardiovascular structure and function, providing a promising breakthrough for improving cardiovascular dysfunction.This review will provide insight into sepsis induced cardiovascular toxicity and reveal directions for further research, contributing to the diagnosis, treatment, and monitoring of SCVDs.out obvious protein coding functions.It has been demonstrated that lncRNAs participate in multitudinous cellular functions and pathological processes by regulating epigenetic, transcriptional, and posttranscriptional levels, and are potential therapeutic targets for septic CVDs.Lipopolysaccharide (LPS) is a glycolipid heteropolymer located on the outer wall of Gram-negative bacteria, and is often used to simulate sepsis toxicity in animal and cell experiments.Zhang et al. [17] focused on key lncRNAs and mRNAs in septic cardiomyopathy by using an LPS-induced rat model.A total of 74 differentially expressed lncRNAs (41 downregulated and 33 upregulated, of which 39 were novel lncRNAs) and 4011 differentially expressed mRNAs (2093 downregulated and 1918 upregulated) were identified by whole genomic RNA sequencing.Subsequent analysis showed that inhibiting the upregulation of lncRNA PVT1 (plasmacytoma variant translocation 1) significantly inhibited the expression of Myd88 and Bcl-2 and promoted the expression of c-Myc and Bax, thereby alleviating myocardial depression in response to LPS.Another study targeted septic vascular dysfunction by using an LPS-stimulated human umbilical vein endothelial cell (HUVEC) model [18].A total of 30,584 differentially expressed lncRNAs (1068 downregulated and 871 upregulated) were screened by the Arraystar Human lncRNA Expression Microarray; among them, CTC-459I6.1 and AL132709.5 were the most downregulated and upregulated lncRNAs, respectively.

The Roles of CircRNAs in SCVDs
CircRNAs (>200 bp) are a class of covalently closed ceRNAs in the cytoplasm that lack 5 ′ -3 ′ polarity or poly-A tails, which contributes to higher stability than linear RNAs (including lncRNAs and miRNAs) [62].CircRNAs are expected to be ideal biomarkers for disease diagnosis due to their stability and highly conserved characteristics.An increasing number of studies have screened significantly differentially expressed circRNAs in septic CVDs by high-throughput sequencing to find candidate diagnostic biomarkers.A recent study identified 11 differentially expressed circRNAs (7 up-and 4 downregulated expression) and 78 differentially expressed miRNAs (54 up-and 24 downregulated expression) in LPS-injected septic shock rat hearts, most of which were closely associated with sepsis cardiac depression [63].Simultaneously, another study reported 801 dysregulated circRNAs (373 up-and 428 downregulated expression) and 4966 dysregulated mRNAs (2063 up-and 2903 downregulated expression) in the aortic tissue of LPS-injected septic rats, most of which were significantly enriched in the calcium signaling pathway [64].Although high-throughput sequencing can effectively screen certain candidate genes, their regulatory mechanism and diagnostic value need to be further verified from bench to bedside.
The circRNA TLK1 (circTLK1, circ_009932) has recently been shown to be significantly upregulated in cecal ligation puncture (CLP)-induced septic rat hearts [65].CircTLK1 acts as a ceRNA competitor of miR-17-5p.The overexpression of circTLK1 is related to downregulated miR-17-5p and increased levels of PARP1 and HMGB1, which consequently leads to mitochondrial dysfunction and DNA oxidative damage in LPS-treated human cardiomyocytes.Similarly, circRNA PTK2 was highly expressed in the hearts of CLP mice, and in LPS-exposed human umbilical vein endothelial cells (HUVECs) and human vascular smooth muscle cells (HUVAMCs), enhanced expression of circRNA-0044073 promotes the proliferation of vascular endothelial and smooth muscle cells, thereby alleviating atherosclerosis [66].CircRNA-0044073 activates the JAK/STAT signaling pathway by sponging miR-107, as evidenced by RNA-pulldown and dual-luciferase reporter assays.Interestingly, exosomes derived from mesenchymal stem cells alleviate cardiotoxicity damage by upregulating the circRTN4/miR-497-5p/MG53 axis, and circRTN4 acts as a functional medium to suppress oxidative stress in CLP rats and LPS-treated H9C2 cells [67].The circRNAmediated ceRNA networks regulate cardiovascular toxicity in sepsis, as shown in Table 3 (Ref.[65][66][67][68]) and Fig. 3.

The Roles of MiRNAs in SCVDs
MiRNAs are highly conserved and small ncRNAs with a length of approximately 21 nucleotides that can control many developmental and cellular processes in eukaryotes [69].RNA polymerases II and III transcribe pre-miRNAs to form precursors, which then undergo complex slicing and splicing events to synthesize mature miRNAs.MiRNAs regulate biological functions through the silencing complex (RISC) induced by RNA, which activates the complex to target miRNA-specified mRNAs [70].Recently, Liu et al. [71] identified 19 different expression miRNAs (5 downregulated, 14 upregulated) and 323 different expression mRNAs (11 downregulated, 312 upregulated) in RAW264.7 cells under RT conditions, and 713 miRNA-mRNA networks were enrolled in the T-cell receptor, MAPK, and JAK-STAT signaling pathways.TargetScan prediction and validation experiments revealed that miR-155-3p could bind to GAB2 and reduce TNF-α secretion.Additionally, curcumin (a natural polyphenolic compound) downregulated miR-155 levels in LPS-treated RAW264.7 and THP-1 cells, and promoted macrophage survival and inhibited inflammatory cytokine release (TNF-α and IL-6) [72].

Inflammation
The typical clinical phenotypes of sepsis are systemic inflammatory response syndrome (SIRS), which results in fever, tachypnea, tachycardia, and peripheral leukocytosis and is a dysregulated host response to infection that leads to a hyperinflammatory cytokine storm and even immunodepression [78].Sepsis consists of two stages, acute immune activation and chronic immune depression.During the initial activation phase of sepsis, necrotic tissue and microorganisms produce damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), which then activate pattern recognition receptors (PRRs, such as TLRs) on the cytomembrane, triggering a series of intracellular signal events and leading to a cascade of release of inflammatory factors (such as NF-κB, IL-6, TNF-α, HMGB1, and NLRP3).Mounting evidence suggests that ncRNAs are involved in the initiation and progression of sepsis-activated inflammation, as shown in Fig. 4.
The lncRNA ribonucleic acid nuclear paraspeckle assembly transcript 1 (NEAT1) was significantly increased in LPS-treated C57 mice and HL-1 mouse cardiomyocytes [42,79].Silencing NEAT1 inhibited inflammationmediated cardiomyocyte apoptosis, and this protective effect was similar to that of miR-144-3p overexpression [42].Both in vivo and in vitro experiments indicated that NEAT1 was an upstream regulator of NF-κB and a ceRNA of miR-144-3p.The lncRNA MAP kinase-activated protein kinase 5 antisense gene protein 1 (MAPKAPK5-AS1) was significantly upregulated in LPS-treated SD rats and H9C2 cells [39].Knockdown of MAPKAPK5-AS1 inhibited inflammatory response by targeting miR-124-3p to downregulate the expression of E2F3.Besides, the lncRNA cardiac hypertrophy related factor (CHRF) was significantly upregulated Abnormal circulating ncRNAs can be used as biomarkers to evaluate the risk, severity, and prognosis of sepsis.Gui et al. [21] found that the plasma lncRNA antisense ncRNA in the INK4 locus (ANRIL) was significantly elevated in sepsis patients (aged 56.6 ± 13.0 years) compared with healthy controls and was accompanied by decreased miR-125a levels.A high plasma ANRIL/miR-125a ratio was an independent predictor of decreased cumulative survival and increased 28-day mortality.Another study showed that plasma lncRNA H19 was significantly decreased in sepsis patients (aged 71.3 ± 9.7 years), which was accompanied by elevated miR-874 levels [30].Positively regulating H19 or negatively regulating miR-874 blunts LPS-mediated cardiomyocyte apoptosis.Aquaporin protein 1 (AQP1) acts as the target of miR-874 and is regulated by H19.Moreover, AQP1 can be regulated by the lncRNA FGD5-AS1/miR-133a-3p axis in LPS-treated HL-1 cells, protecting cardiomyocytes from septic injury [26].The upregulation of FGD5-AS1 increases the expression of AQP1 by downregulating miR-133a-3p expression.

Oxidative Response
Along with inflammation, oxidative stress-mediated injury participates in detrimental pathways activated during sepsis-related organ dysfunction, ultimately causing multiple organ failure and death.Sepsis accelerates the excessive production of reactive oxygen species (ROS) and the disruption of antioxidant systems, disequilibrating redox homeostasis to a prooxidative state.Once the pathogencaused prooxidant state is established, the subsequent cascade release of ROS exacerbates further self-damage to injured cells, independent of the original pathogen itself.Excessive ROS levels directly cause cardiomyocyte apoptosis, mitochondrial damage and cardiac insufficiency in the septic myocardium, simultaneously, it leds to glycocalyx degradation, increased permeability and impaired vasoreactivity in the septic vascular endothelium [80].Accumulating knowledge implicates that ceRNA networks are involved in regulating the pathogenic process of sepsisrelated CVDs, as shown in Fig. 5.

Endothelial Dysfunction
The vascular endothelium acts as an important biological barrier of the circulatory system that controls systemic fluid regulation and plays key roles in hemodynamics, circulatory immunity, and tissue metabolism [81].Endothe-lial dysfunction occurs in the early stage of sepsis toxic injury, which triggers the circulatory system and causes insufficient blood supply to vital organs, followed by the collapse of the immune system leading to systemic inflammation [82].Sepsis-induced endothelial dysfunction increases the risk of CVDs, but the specific molecular mechanism is not clear.Singh et al. [18] examined the expression of lncRNAs and mRNAs in HUVECs stimulated with LPS, and 30,584 lncRNAs (1068 downregulated and 871 upregulated) and 26,106 mRNAs (536 downregulated and 733 upregulated) were significantly differentially ex-pressed; among them, CTC-459I6.1 was the most downregulated, and AL132709.5 was the most upregulated lncRNA, which are associated with sepsis-induced endothelial dysfunction.

Macrophage Polarization
Macrophages are involved in the regulation of innate and acquired immunity and can be transformed into classically (M1) and alternatively (M2) activated macrophages under different pathophysiological conditions.M1/M2 polarization of macrophages is positively correlated with the severity of sepsis, M1-type macrophages release proinflammatory factors to participate in the occurrence and maintenance of sepsis, and M2-type macrophages release antiinflammatory factors to participate in the resolution of sepsis [83].Downregulation of lncRNA PVT1 suppresses M1type macrophage polarization [59].PVT1 inhibited miR-29a expression and upregulated HMGB1 expression, sub-sequently aggravating sepsis-caused myocardial injury in LPS-treated C57BL/6 mice and primary macrophages.A recent study reported that MALAT1 was downregulated in patients with sepsis and LPS-induced RAW264.7 murine macrophages, while hsa-miR-346 was upregulated [55].MALAT1 promoted the expression of SMAD3 by downregulating hsa-miR-346 levels.The viability of RAW264.7 cells was inhibited by MALAT1 and promoted by hsa-miR-346.Moreover, knockout of NEAT1 significantly decreased the levels of IL-1β, IL-6, TNF-α and COX-2 in ox-LDL-stimulated THP-1 human macrophages, and the NEAT1/miR-342-3p/NFIA axis may be enrolled in the inflammatory response and lipid uptake in atherosclerosis [84].

Mitochondrial Dysfunction
Mitochondria are not only the core organelles that produce ROS, but also the energy metabolism factories that produce adenosine triphosphate (ATP).Sepsis promotes the production of ROS and inhibits the production of ATP in myocardial mitochondria, resulting in mitochondrial biogenesis (apoptosis and mitophagy), oxidative stress, calcium overload, energy imbalance, and cardiac dysfunction.In recent years, the epigenetic regulatory mechanisms in sepsis-related CVDs, including ncRNA regulation, chromatin remodeling, DNA methylation, and histone modifications, have attracted great attention from the life science community [86].Evidence-based studies indicate that ceRNA networks play crucial roles in biological activities, especially in the regulation of mitochondrial function in septic CVDs, as shown in Fig. 5.

Endoplasmic Reticulum Stress
In response to misfolded proteins in the endoplasmic reticulum (ER) and dysregulation of calcium home-ostasis, ER stress (ERS) acts as a protective stress response by reducing intracellular unfolded proteins to prevent their aggregation [88].Activating transcription factor 6 (ATF6), pancreatic endoplasmic reticulum kinase (PERK), and inositol-requiring enzyme 1α (IRE1α) signaling are major ERS-related pathways involved in the ER overload response, unfolded protein response, and caspase-12-mediated apoptosis.Mitochondria-associated membranes (MAMs) located on the ER are the essential sites contacting mitochondria to maintain mitochondrial function and mediate bidirectional communications, including mitochondrial DNA synthesis and fission, lipid biosynthesis, and calcium exchange [89].
The lncRNA discrimination antagonizing ncRNA (DANCR) is recognized as a protective factor for myocardial infarction, and a recent study revealed its mechanism in ERS-induced myocardial injury [90].The upregulation of DANCR promotes autophagy and inhibits apoptosis to protect cardiomyocytes against tunicamycincaused ERS injury.Mechanistically, DANCR enhances autophagy and ERS to maintain cellular homeostasis, leading to a reduction in apoptosis by adsorbing miR-6324.In addition, lncRNA MALAT1 affects ERS in CLP-induced septic mice and LPS-challenged HUVECs via the miR-150/NF-κB pathway, leading to endothelial damage [58].Downregulation of MALAT1 inhibited the expression of the ERS-associated proteins GRP78 and CHOP, along with the apoptosis-associated proteins caspase-3 and Bax-1, and these effects could be blocked by a miR-150 antagonist through regulation of NF-κB.These data suggest that the MALAT1/miR-150/NF-κB axis may contribute to LPSinduced ERS in septic CVDs.

Apoptosis
Apoptosis refers to autonomous programmed cell death, which is strictly controlled by genes to maintain cellular homeostasis.Sepsis promotes an uncontrolled inflammatory cascade and immunocyte apoptosis that leads to immune paralysis.Targeted regulation of apoptosis can improve the survival of patients with sepsis [91].Excessive apoptosis of immune cells induces immunosuppression, and apoptotic cardiovascular cells have the potential to exacerbate secondary heart failure and microvascular dysfunction during sepsis.Although apoptosis is a crucial event in the pathology of sepsis-induced CVDs, the underlying mechanisms are not fully understood.Increasing knowledge indicates that ncRNAs are involved in the regulation of apoptosis in sepsis-related CVDs, as shown in Fig. 7.
In LPS-stimulated H9C2 cells and septic patients, the level of miR-642a was significantly decreased [35].Silencing of the lncRNA lung cancer-related transcript 1 (LU-CAT1) attenuated LPS-induced cardiomyocyte apoptosis, and LUCAT1 could regulate the secretion of ROCK1 by interacting with miR-642a.LUCAT1 could function as a sponge for miR-642a to modulate the expression of ROCK1 in LPS-exposed H9C2 cells.Beyond that, the plasma levels of the lncRNA cardiac autophagy inhibitory factor (CAIF) and miR-16 were decreased in patients with chronic heart failure (CHF) caused by sepsis [22].The overexpression of CAIF or miR-16 repressed LPS-caused cardiomyocyte apoptosis by enhancing Bcl-2 levels and reducing Bax levels, and the expression of IL-6, CXCL1, and CCL2 was downregulated.CAIF upregulation inhibited cardiomyocyte inflammation and apoptosis by demethylating miR-16 in sepsis-associated CHF.In addition, the lncRNA hox transcript antisense RNA (HOTAIR) was observed to be upregulated in LPS-treated H9C2 cells and monocytes, which targets miR-1-3p and miR-211 to regulate IL-6 and IL-6R, respectively [32,53].These results showed that the HOTAIR-miR-1-3p/ miR-211-IL-6 pathway was involved in sepsisrelated cardiovascular toxicity.

Pyroptosis
Pyroptosis has been identified as a specialized programmed cell death caused by an uncontrolled cascade of inflammatory factors and is one of the important mechanisms involved in septic CVDs.In contrast to apoptosisinduced nuclear destruction, a typical feature of pyroptosis is that the nucleus usually remains intact.Inflammasomes (such as NLRP3, also known as NACHT, LRR, and PYD domain-containing protein) and LPS can activate certain proteins in the caspase family (caspase-1, -4, -5, and -11) to proteolytically cleave N-terminal of Gasdermin D (GSDMD) [78].IL-18 and IL-1β can be activated by caspase-1, thereby aggravating inflammatory injury.Cleaved GSDMD is translocated to the membrane to form pores, resulting in cell swelling, membrane blebbing, DNA fragmentation and eventual cell disassembly.Wang et al. [47] studied the role of lncRNA X-inactive spe- cific transcript (XIST) in the modulation of sepsis-caused myocardial pyroptosis.XIST expression was upregulated and miR-150-5p expression was downregulated in CLPinduced SD rat hearts and LPS-exposed H9C2 cardiomyocytes.Silencing XIST inhibited the LPS-mediated upregulation of pyroptotic proteins (NLRP3, cleaved caspase-1, and ASC) in H9C2 cells by regulating miR-150-5p and inhibiting c-Fos expression.Knockdown of XIST reduced pyroptosis-caused cardiac dysfunction in septic rats.c-Fos coupled with the promoter of the thioredoxin-interacting protein (TXNIP) gene and then promoted the expression of TXNIP.Another study showed that XIST bound to miR-7a-5p downregulated PGC-1α and TFAM expression, thereby improving LPS-stimulated mouse cardiomyocyte apoptosis and inflammatory cytokine release [48].Taken together, these data suggest that XIST affects pyroptosis-mediated septic cardiovascular injury by regulating the miR-150-5p/c-Fos/TXNIP and miR-7a-5p/PGC-1α/TFAM axes, as shown in Fig. 7.

Conclusions
Accumulating evidence has shown that ceRNA networks play vital roles in the pathophysiological progression of septic cardiomyopathy and vascular paralysis, as shown in Fig. 8.As mentioned previously, lncRNAs and circR-NAs regulate miRNAs by sponging or decoying miRNAs in sophisticated ceRNA networks.MiRNA activation or inhibition leads to the degradation or renaturation of target mRNAs, thereby modulating the transcriptional and translational modification of downstream genes.Based on existing knowledge, lncRNAs MALAT1, GAS5, ZFAS1, and XIST and the circRNAs TLK1 and ANKRD36, are related to the pathogenesis of septic cardiomyopathy by regulating inflammation, oxidative response, endothelial dysfunction, macrophage polarization, apoptosis and pyroptosis, along with metabolic energy impairment and ERS.Moreover, the lncRNAs LUADT1, HULC, and circRNA-0044073 are involved in septic vascular paralysis by modulating endothelial cell apoptosis and the inflammatory cytokine cascade.
Understanding the ceRNA networks contributes to further understanding of the molecular mechanisms of SCVDs and is expected to seek breakthroughs in the ncRNA-dependent treatment of septic CVDs.Based on the mechanisms discovered, it may be possible to focus on positively or negatively regulating key lncRNAs or circRNAs to prevent the pathological progression of SCVDs at the translational and posttranscriptional levels.Simultaneously, it might also be a good idea to restore or block certain miRNA functions to modulate target mRNAs for subsequent biological effects.On the other hand, previous studies partially explained the molecular mechanisms underlying the biological effects of SCVDs, suggesting that we can prevent cardiovascular dysfunction in sepsis by suppressing inflammation and oxidative stress, restoring endothelial and mitochondrial function, and inhibiting apoptosis and pyroptosis [8,72,80,81,86,88].
Despite the great potential of the ceRNA network as a therapeutic target and diagnostic biomarker for SCVDs, there are numerous limitations affecting its clinical applications.In the first place, a great quantity of animal and cell experiments have demonstrated that ceRNA axes play important regulatory roles in SCVD models in vivo and in vitro, but there is a lack of further confirmation in largesample clinical trials, especially in multicenter prospective studies.In addition, the clinical characteristics of sepsis are complicated and involve multiple systems and organs.Using only a certain ncRNA for early diagnosis and prognostic monitoring cannot fully reflect the severity and outcome of SCVDs, and a comprehensive evaluation should be combined with disease progression and treatment feedback.Moreover, the ceRNA network is not a simple one-to-one linear axis but a crisscross and interrelated map with multiple targets and pathways.The same lncRNA or circRNA can act on different miRNAs, and different miRNAs can regulate the same target mRNA, thereby mediating different biological effects.Consequently, a satisfactory therapeutic effect cannot be obtained through specific ncRNAtargeted therapy, and multiorgan support and early bundled treatment are needed.Although there are still limitations in the transformation from bench to bedside, it is undeniable that revealing the ceRNA network is beneficial for deciphering the pathogenic mechanism of SCVDs and providing directions for further clinical diagnosis and treatment.

Fig. 2 .
Fig. 2. The regulatory mechanism of the competitive endogenous RNA networks in transcription, translation, and epigenetics.LncRNA regulates transcription by splicing and degrading RNA, while posttranscriptional regulation is controlled by decoy and sponge proteins, as well as epigenetic modification.CircRNA regulates transcription and translation by binding to miRNA and interacting with RNA-binding protein, particularly in certain circRNA can code protein.Both lncRNA and circRNA can serve as competitive endogenous RNA that bind with miRNA to regulate the translation of targeted mRNA, thereby inhibiting mRNA translation and promoting mRNA degradation.See text for details.circRNA, circular RNA; lncRNA, long non-coding RNA; miRNA, microRNA; mRNA, messenger RNA; UTR, untranslated regions.

Fig. 8 .
Fig. 8.The lncRNA-and circRNA-associated competitive endogenous RNA networks in septic cardiovascular dysfunction.The regulatory mechanisms and potential functions of ceRNA networks in septic cardiomyopathy and vascular paralysis by regulating inflammation, oxidative response, endothelial dysfunction, macrophage polarization, apoptosis and pyroptosis, along with metabolic energy impairment and endoplasmic reticulum stress.See text for details.