Pellino1 deficiency reprograms cardiomyocytes energy metabolism in lipopolysaccharide-induced myocardial dysfunction

Abstract

Pellino1 has been shown to regulate proinflammatory genes by activating the nuclear factor kappa B (NF-κB) and Toll-like receptor (TLR) signaling pathways, which are important in the pathological development of lipopolysaccharide (LPS)-induced myocarditis. However, it is still unknown whether silencing Pellino1 (si-Pellino1) has a therapeutic effect on this disease. Here, we showed that silencing Pellino1 can be a potential protective strategy for abnormal myocardial energy metabolism in LPS-induced myocarditis. We used liquid chromatography electrospray–ionization tandem mass spectrometry (LC–MS/MS) to analyze samples from si-Pellino1 neonatal rat cardiac myocytes (NRCMs) treated with LPS or left untreated. After normalization of the data, metabolite interaction analysis of matched KEGG pathway associations following si-Pellino1 treatment was applied, accompanied by interaction analysis of gene and metabolite associations after this treatment. Moreover, we used western blot (WB) and polymerase chain reaction (PCR) analyses to determine the expression of genes involved in regulating cardiac energy and energy metabolism in different groups. LC–MS-based metabolic profiling analysis demonstrated that si-Pellino1 treatment could alleviate or even reverse LPS-induced cellular damage by altering cardiomyocytes energy metabolism accompanied by changes in key genes (Cs, Cpt2, and Acadm) and metabolites (3-oxoocotanoyl-CoA, hydroxypyruvic acid, lauroyl-CoA, and NADPH) in NRCMs. Overall, our study unveiled the promising cardioprotective effect of silencing Pellino1 in LPS-induced myocarditis through fuel and energy metabolic regulation, which can also serve as biomarkers for this disease.

Alterations of the gut microbiome and metabolic profile in CVB3-induced mice acute viral myocarditis

“…As an important bile acid which can decrease the expression of pro-inflammatory cytokines and chemokines [ 50 ], taurocholic acid may promote the healing of AVMC. As the main source of energy for cardiac mechanical work, fatty acid (FA) metabolomics such as FFA (16:1) were decreased in AVMC group, consistent with previous findings in bacterial myocarditis [ 51 ]. While Phosphate sugars metabolomics such as D-Glucose 6-Phosphate increased, indicating improvement of cardiomyocytes energy demand in AVMC.…”

Biology of Pellino1: a potential therapeutic target for inflammation in diseases and cancers

“…In an LPS-induced myocarditis model, Peli1 was activated and promoted pro-inflammatory genes expression ( 129 ). Si-Peli1 Treatment alleviated or even reversed LPS-induced cellular injury by modulating cardiomyocyte energy metabolism and altering the expression of key genes ( Cs, Cpt2 , and Acadm ) and metabolites (3-oxoocotanoyl-CoA, hydroxypyruvic acid, lauroyl-CoA, and nicotinamide adenine dinucleotide phosphate) ( 129 ). In the context of diabetes-induced cardiovascular response, Peli1 elevates its interaction with HSP90, competitively inhibiting IRE1α binding to HSP90 and promoting IRE1α phosphorylation and ER stress.…”

“…Gene therapy targeting Peli1 has also shown promise in improving perfusion and cardiac function in ischemic infarction models ( 95 , 105 ). In an LPS-induced myocarditis model, Peli1 activatio was associated with promoting pro-inflammatory genes, and si-Peli1 treatment alleviated or reversed LPS-induced cellular injury by altering cardiomyocyte energy metabolism ( 129 ). MiRNAs have been explored as regulators of Peli1 and human umbilical cord mesenchymal stem cell-derived extracellular vesicles modified with miR-30c-5p effectively suppress Peli1 expression and inhibit papillary thyroid carcinoma progression in vitro and in vivo ( 103 ).…”

“…In an LPS-induced myocarditis model, Peli1 was activated and promoted pro-inflammatory genes expression (129). Si-Peli1 Treatment alleviated or even reversed LPS-induced cellular injury by modulating cardiomyocyte energy metabolism and altering the expression of key genes (Cs, Cpt2, and Acadm) and metabolites (3oxoocotanoyl-CoA, hydroxypyruvic acid, lauroyl-CoA, and nicotinamide adenine dinucleotide phosphate) (129). In the context of diabetes-induced cardiovascular response, Peli1 elevates its interaction with HSP90, competitively inhibiting IRE1a binding to HSP90 and promoting IRE1a phosphorylation and ER stress.…”