At the moment, there is no specific therapy for septic cardiomyopathy. However, studying the molecular characteristics of sepsis-induced cardiomyopathy is a promising approach for elucidating pathophysiological mechanisms and identifying specific targets for new therapeutic interventions in septic patients with a specific condition (Pinto et al., 2021). Nevertheless, a small number of proteins, metabolites, and molecular pathways have been investigated. Previously published research has only provided insight into the molecular pathways behind septic cardiac dysfunction using a rat CLP model (Hinkelbein et al., 2010). The pathophysiological causes of septic cardiomyopathy must be understood to develop a viable strategy for dealing with sepsis-induced cardiomyopathy and the rising septic death rate (Landesberg et al., 2012; Sturgess et al., 2010). Our research generated a sepsis mouse model based on echocardiography, heart morphology, and the expression of myocardial enzymes (Hoffman et al., 2019; Hollenberg & Singer, 2021). The integrated proteomics and metabolomics investigation of septic cardiomyopathy tissues was confirmed based on the underlying mechanism in the protein-metabolite interaction pathway.
Our findings in the proteome analysis add to the body of knowledge about the control of DE proteins produced in sepsis-affected cardiac tissues. The Snca, Prpsap1, Sp1, Qsox1, Lcp1, Arhgdib, Cfh, Gda, H1-3, and Prph were elevated among the 118 DE proteins compared to the control group. Prpsap1, Qsox1, and Prph proteins are three unique upregulated DE proteins that have never been described before. The Snca-null mice were less able to control infection after being inoculated intravenously with Salmonella typhimurium in previous studies (Tomlinson et al., 2017). The autophagic-lysosomal pathway is also linked to Snca (Mitroi et al., 2017). GATA-2 and Sp1 have been shown in studies to mediate the action of LPS via cAMP and calcium signaling pathways (Liu et al., 2007). Sp1 regulates LPS-induced cardiomyocyte apoptosis via the ZFAS1/Notch signaling pathway, suggesting that both pathways could be therapeutic targets for sepsis-induced cardiac damage, according to the current study (Chen et al., 2021). Activating the SP1/RCN2/ROS signaling pathway may also increase LPS-induced endothelial cell pyroptosis (Zhao et al., 2021). The Cfh gene, which corresponds with sepsis, has been discovered as a possible biomarker targeting P. aeruginosa infection in critically unwell patients (Li et al., 2020).
The importance of metabolic reprogramming in the onset and progression of cardiovascular disease has been well characterized (Chang et al., 2021). Since correlation plays an integral part in disease progression, we assume it may be a significant cause. Sepsis-related metabolic alterations in the heart were discovered over the study's metabolic investigation. To name just a few: Arachidonic acid, purine, linoleic acid, linoleic acid-methane, glucose-ammonia-phosphate, amino-sugar-and-nucleotide-sugar metabolism, glyoxylate and dicarboxylate metabolism, gluconeogenesis, D-glutamine, and D-glutamate metabolism. Glyoxylate and dicarboxylate metabolism were also linked to sepsis in the first place. In recent studies, methane metabolism has been linked to sepsis, which has an antioxidative, anti-inflammatory, and anti-apoptotic effect on sepsis-induced organ harm (Jia et al., 2018; Li Z et al., 2019; Zhang et al., 2016).
A lack of study on cardiac tissue meant that we could contribute a new layer of knowledge to the heart. Bacteria-stimulated macrophages rely heavily on starch and sucrose metabolic abnormalities as pathogenesis of sepsis (Xu et al., 2021). The glutamate/glutamine ratio and plasma glutamate concentrations in patients who die from septic shock due to severe liver failure were shown to be significantly lower in the first 24 hours of septic shock, according to research (Poeze et al., 2008). Septic cardiomyopathy may differ from other forms of cardiomyopathy, as evidenced by the findings of our study. Sepsis pathophysiology may be better understood, and new potential biomarkers may be discovered as a result.
In addition, the underlying process is a part of the protein-metabolite interplay pathway. Our findings shed light on new ways in which platelet activation and mineral absorption may influence heart metabolism. Many diseases can be better detected and treated early with metabolomic investigations, which provide a precise assessment of individual metabolic reactions to pathophysiological stimuli (Bjerkhaug et al., 2021). When activated in abnormal circumstances, they can induce blood clots in the circulatory system, a leading cause of death in the elderly. It is important to note that platelets also play an essential part in regulating the immune system and the fight against microbial infection (Salamah et al., 2018). Septic cardiomyopathy was previously linked to several genes in the protein-metabolite interaction pathway that was not previously associated with platelet activation factors TXA2, Fgg, Fgb, Rap1a, Plcb3, TXA2, and Rap-1A. Additionally, our discoveries include previously unreported proteins and their metabolites. Rap1a, a GTPase, connects external stimuli to intracellular responses by inducing changes in effector proteins (Wang et al., 2015; Yan et al., 2008). Research has shown that cardiac fibroblasts' response is mediated by Rap1a (Burr & Stewart, 2021). There are four distinct isoforms of phospholipase C-β3 (PLC-β3), which are PLC-β1, 2, 3, and 4, with PLC-β1 being the most abundant. The enzyme is regulated by the G protein-coupled receptor (GPCR) (Rhee & Bae, 1997). PLC-β3 was a transcription factor that regulated proliferation, survival, and angiogenesis (Ha et al., 2016). Previous research established that synergistic stimulation of platelet agonists such as ADP, collagen, and TXA2 is required for LPS-triggered activation (Li RH et al., 2019; Nocella et al., 2017). Exosomes with high concentrations of NADPH are generated in heart blood arteries following platelet activation via ROS exposure; these exosomes are absorbed by endothelial cells, resulting in cell death and cardiac failure (Monteiro et al., 2017). Platelet activation modulates cardiac contractility by limiting leukocyte adherence to the endothelium (Loscalzo & Welch, 1995). An iron-dependent form of cell death caused by the erastin molecule is distinct from apoptosis, necroptosis, pyroptosis, and necroptosis in cell death mechanisms (Wang et al., 2020). Ferroptosis has been linked to sepsis-induced cardiac dysfunction, and inhibiting it may help ameliorate at least partially through the TLR4/NF-κB signaling pathway (Xiao et al., 2021). A decline in ventricular systolic function, an increase in heart damage indicators, and an upregulation of ferritin light chain (Ftl1) and heavy chain (Fth1) expression were all seen in mice treated with CLP in previous research. Mineral absorption, Ftl1, Ftl1, ferritin, and L-2-Aminoglutaramic acid were all implicated in this considerable shift.
As a whole, our findings suggest that proteins and the metabolites they target may interact in unexpected ways. Although this study has its flaws, it is nonetheless an important one. No other technique or database was used to validate the analysis results, and the animal model does not capture all aspects of the underlying physical changes. Septic cardiomyopathy-induced metabolic problems have not yet been proven to have distinct functions for associated differential proteins in the pathophysiology of these illnesses. As a result, future considerations for accurate confirmation of these DE metabolites and proteins DE are an absolute necessity.
In conclusion, we sought to comprehend another form of septic cardiomyopathy by performing a protein-metabolite interaction investigation on cardiac tissues. The complicated functional roles of network components suggest that they may represent potential treatment targets for cardiac metabolic diseases and require additional investigation; these findings demonstrate both overlapping metabolic pathways affected in cardiac tissues and provide insight into the metabolic changes associated with sepsis-induced heart dysfunction. Once the relationship between the changed metabolites/metabolisms and the underlying pathophysiology of sepsis is established, this may allow for therapeutic approaches that target several organs or single tissues. Our findings will aid in identifying novel biomarkers and treatment methods for sepsis.