A circular network of purine metabolism as coregulators of dilated cardiomyopathy

Abstract

Background The crosstalk of purine biosynthesis and metabolism exists to balance the cell energy production, proliferation, survival and cytoplasmic environment stability, but disorganized mechanics of with respect to developing heart failure (HF) is currently unknown. Methods We conducted a multi-omics wide analysis, including microarray-based transcriptomes, and full spectrum metabolomics with respect to chronic HF. Based on expression profiling by array, we applied a bioinformatics platform of quantifiable metabolic pathway changes based on gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), Shapley Additive Explanations (SHAP), and Xtreme Gradient Boosting (XGBoost) algorithms to comprehensively analyze the dynamic changes of metabolic pathways and circular network in the HF development. Additionally, left ventricular tissue from patients undergoing myocardial biopsy and transplantation were collected to perform the protein and full spectrum metabolic mass spectrometry. Results Systematic bioinformatics analysis showed the purine metabolism reprogramming was significantly detected in dilated cardiomyopathy. In addition, this result was also demonstrated in metabolomic mass spectrometry. And the differentially expressed metabolites analysis showing the guanine, urea, and xanthine were significantly detected. Hub markers, includes IMPDH1, ENTPD2, AK7, AK2, and CANT1, also significantly identified based on XGBoost, SHAP model and PPI network. Conclusion The crosstalk in the reactions involved in purine metabolism may involving in DCM metabolism reprogramming, and as coregulators of development of HF, which may identify as potential therapeutic targets. And the markers of IMPDH1, ENTPD2, AK7, AK2, and CANT1, and metabolites involved in purine metabolism shown an important role.

Comprehensive Metabolomic Analysis of Human Heart Tissue Enabled by Parallel Metabolite Extraction and High-Resolution Mass Spectrometry

“…Additionally, pathway analysis was performed to highlight the coverage of various metabolic pathways covered by our combined approach (Figure B). Among the detected pathways were Purine Metabolism and Glycerophospholipid Metabolism, key pathways involved in the metabolic processes of the human heart. − It is important to note that metabolomic pathway analyses should be integrated with other “omic” analyses, such as proteomics and transcriptomics, to better understand alterations within the pathway. ,, To illustrate the enhanced coverage of the metabolome by using our approach, we selected a pathway known to be altered in many cardiac diseases (purine metabolism) ,− and highlighted the extraction method(s) in which each metabolite was found (Figure C). Remarkably, one of the metabolites was observed in only a single extraction – inosine diphosphate (IDP).…”

High Stretch Modulates cAMP/ATP Level in Association with Purine Metabolism via miRNA–mRNA Interactions in Cultured Human Airway Smooth Muscle Cells

“…In particular, other than serving as building blocks for DNA, purine nucleotides such as ATP are crucial for providing cellular energy, intracellular signaling, and cofactors to promote cell survival and proliferation [49]. Several diseases have also been linked to purine metabolism [54]. In airways, purine is not only involved in the normal energy flow but can also serve as a VILI marker in bronchoalveolar lavage fluid [55][56][57].…”

“…In this study, we found that ASMCs responded to high stretch with marked changes in interactions between certain miRNAs and their target genes, including miR-370-5p-PDE4D, miR-543-PDE4D, miR-29b-3p-PDE7B, miR-370-5p-AK7, miR-148a-3p-AK4, miR-194-5p-ENPP1, and miR-146-5p-NME1, which may all impact the mitochondrial respiratory function. Among them, miR-370-5p-AK7 is more likely to be involved in ATP synthesis inside ASMCs during high stretch because AK7 is known to function as phosphotransferase in energy homeostasis, and as adenylate kinase to catalyze the production and breakdown of adenine nucleotide in a reversible transfer method [54]. It has also been shown that depletion of AK7 protein will lead to impaired mitochondrial respiratory function, especially the synthesis of ATP [61].…”

Shenfu injection improves isoproterenol-induced heart failure in rats by modulating co-metabolism and regulating the trimethylamine-N-oxide - inflammation axis

“…The produced xanthine is converted into uric acid by xanthine oxidase, which generates a significant amount of superoxide anions, causing cellular damage. Under low oxygen environments, the byproducts of the breakdown of adenosine and inosine serve as more efficient energy sources than extracellular glucose, thereby slowing the build-up of nicotinamide adenine dinucleotide (NADH) and offering a degree of protection to the cells ( Wang G. et al, 2022 ). In the present study, hypoxanthine and deoxyinosine levels were significantly increased in the HF rat model, indicating the presence of an energy imbalance in the HF rat model, which is consistent with research findings ( Berry and Hare, 2004 ).…”