Identification of metabolic pathways underlying FGF1 and CHIR99021-mediated cardioprotection

Xu, Bing; Li, Fan; Zhang, Wenjing; Su, Yajuan; Tang, Ling; Li, Pengsheng; Joshi, Jyotsna; Yang, Aaron; Liu, Dong; Wang, Zhao; Wang, Shu; Xie, Jingwei; Gu, Haiwei; Zhu, Wuqiang

doi:10.1016/j.isci.2022.104447

Cited by 6 publications

(5 citation statements)

References 99 publications

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“…The metabolism of CM in ischemic heart tissues is marked by a switch from mitochondrial fatty acid oxidation to glycolysis, which contributes to ATP production essential for maintaining CM survival under these conditions [2,[24][25][26] . Surprisingly, scMetabolism analysis suggested that surviving CM suppressed glycolysis/gluconeogenesis and pyruvate metabolism.…”

Section: Discussionmentioning

confidence: 99%

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Identification of the metabolic state of surviving cardiomyocytes in the human infarcted heart by spatial single-cell transcriptomics

et al. 2023

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Background and purpose: The metabolic status of surviving cardiomyocytes (CM) in the myocardial tissues of patients who sustained myocardial infarction (MI) is largely unknown. Spatial single-cell RNA-sequencing (scRNA-seq) is a novel tool that enables the unbiased analysis of RNA signatures within intact tissues. We employed this tool to assess the metabolic profiles of surviving CM in the myocardial tissues of patients post-MI.Methods: A spatial scRNA-seq dataset was used to compare the genetic profiles of CM from patients with MI and control patients; we analyzed the metabolic adaptations of surviving CM within the ischemic niche. A standard pipeline in Seurat was used for data analysis, including normalization, feature selection, and identification of highly variable genes using principal component analysis (PCA). Harmony was used to remove batch effects and integrate the CM samples based on annotations. Uniform manifold approximation and projection (UMAP) was used for dimensional reduction. The Seurat "FindMarkers" function was used to identify differentially expressed genes (DEGs), which were analyzed by the Gene Ontology (GO) enrichment pathway. Finally, the scMetabolism R tool pipeline with parameters method = VISION (Vision is a flexible system that utilizes a high-throughput pipeline and an interactive web-based report to annotate and explore scRNA-seq datasets in a dynamic manner) and metabolism.type = Kyoto Encyclopedia of Genes and Genomes (KEGG) was used to quantify the metabolic activity of each CM.Results: Analysis of spatial scRNA-seq data showed fewer surviving CM in infarcted hearts than in control hearts. GO analysis revealed repressed pathways in oxidative phosphorylation, cardiac cell development, and activated pathways in response to stimuli and macromolecular metabolic processes. Metabolic analysis showed downregulated energy and amino acid pathways and increased purine, pyrimidine, and one-carbon pool by folate pathways in surviving CM.Conclusions: Surviving CM within the infarcted myocardium exhibited metabolic adaptations, as evidenced by the downregulation of most pathways linked to oxidative phosphorylation, glucose, fatty acid, and amino acid metabolism. In contrast, pathways linked to purine and pyrimidine metabolism, fatty acid biosynthesis, and one-carbon metabolism were upregulated in surviving CM. These novel findings have implications for the development of effective strategies to improve the survival of hibernating CM within the infarcted heart.

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Section: Discussionmentioning

confidence: 99%

“…Little is known about how surviving CM flexibly reprogram their metabolic energy within infarcted heart tissues. Xu et al [2] . recently reported that the metabolic energy of ischemic CM switches from mitochondrial oxidative phosphorylation (OXPHOS) to glycolysis and lactic fermentation.…”

Section: Introductionmentioning

confidence: 99%

Identification of the metabolic state of surviving cardiomyocytes in the human infarcted heart by spatial single-cell transcriptomics

et al. 2023

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“…We isolated fresh tissues from the heart, liver, kidney, intestine, colon, and uterus of mice. Whole-cell lysates were generated from these tissues as described before [21]. The samples were loaded to 10% SDS-PAGE gel and then transferred to a PVDF membrane.…”

Section: Evaluation Of Tenascin-x Expression In Mouse Organs and Huma...mentioning

confidence: 99%

Peptide-Guided Nanoparticle Drug Delivery for Cardiomyocytes

Li,

Taylor,

Shi

et al. 2024

Biology

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Background: Nanoparticles (NPs) have been extensively utilized as a drug delivery system to control the release of therapeutic agents to treat cardiac injuries. However, despite the advantages of utilizing NP-based drug delivery for treating heart diseases, the current delivery system lacks specificity in targeting the cardiac tissue, thus limiting its application. Methods: We created three linear peptides, each consisting of 16–24 amino acids. These peptides were conjugated on the surface of NPs, resulting in the formation of cardiac targeting peptide (CTP)-NPs (designated as CTP-NP1, CTP-NP2, and CTP-NP3). To assess their effectiveness, we compared the binding efficiency of these three CTP-NPs to human and mouse cardiomyocytes. Additionally, we determined their distribution 24 h after injecting the CTP-NPs intravenously into adult C57BL/6J mice. Results: When compared to control NPs without CTP (Con-NPs), all three CTP-NPs exhibited significantly increased binding affinity to both human and mouse cardiomyocytes in vitro and enhanced retention in mouse hearts in vivo. A thorough assessment of the heart sections demonstrated that the binding specificity of CTP-NP3 to cardiomyocytes in vivo was significantly greater than that of Con-NPs. None of the three CTP-NPs were proven to cause cardiomyocyte apoptosis. Conclusions: Biocompatible and safe CTP-NP3 can target the heart via binding to cardiomyocytes. This approach of targeting specific molecules-coated NPs may help in delivering therapeutic compounds to cardiomyocytes for the treatment of heart diseases with high efficacy and low toxicity to other tissues.

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“…In postnatal adult cardiomyocytes, FGF Signaling plays very important role in modulating proliferation; FGF1 is involved in homeostasis and remodeling [ 225 ]. FGFs have multifunctional roles ranging from proliferation, homeostasis to differentiation.…”

Section: Key Cardiac Signaling Pathwaysmentioning

confidence: 99%

The benign nature and rare occurrence of cardiac myxoma as a possible consequence of the limited cardiac proliferative/ regenerative potential: a systematic review

Shafi,

Siddiqui,

Jaffry

2023

BMC Cancer

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Background Cardiac Myxoma is a primary tumor of heart. Its origins, rarity of the occurrence of primary cardiac tumors and how it may be related to limited cardiac regenerative potential, are not yet entirely known. This study investigates the key cardiac genes/ transcription factors (TFs) and signaling pathways to understand these important questions. Methods Databases including PubMed, MEDLINE, and Google Scholar were searched for published articles without any date restrictions, involving cardiac myxoma, cardiac genes/TFs/signaling pathways and their roles in cardiogenesis, proliferation, differentiation, key interactions and tumorigenesis, with focus on cardiomyocytes. Results The cardiac genetic landscape is governed by a very tight control between proliferation and differentiation-related genes/TFs/pathways. Cardiac myxoma originates possibly as a consequence of dysregulations in the gene expression of differentiation regulators including Tbx5, GATA4, HAND1/2, MYOCD, HOPX, BMPs. Such dysregulations switch the expression of cardiomyocytes into progenitor-like state in cardiac myxoma development by dysregulating Isl1, Baf60 complex, Wnt, FGF, Notch, Mef2c and others. The Nkx2–5 and MSX2 contribute predominantly to both proliferation and differentiation of Cardiac Progenitor Cells (CPCs), may possibly serve roles based on the microenvironment and the direction of cell circuitry in cardiac tumorigenesis. The Nkx2–5 in cardiac myxoma may serve to limit progression of tumorigenesis as it has massive control over the proliferation of CPCs. The cardiac cell type-specific genetic programming plays governing role in controlling the tumorigenesis and regenerative potential. Conclusion The cardiomyocytes have very limited proliferative and regenerative potential. They survive for long periods of time and tightly maintain the gene expression of differentiation genes such as Tbx5, GATA4 that interact with tumor suppressors (TS) and exert TS like effect. The total effect such gene expression exerts is responsible for the rare occurrence and benign nature of primary cardiac tumors. This prevents the progression of tumorigenesis. But this also limits the regenerative and proliferative potential of cardiomyocytes. Cardiac Myxoma develops as a consequence of dysregulations in these key genes which revert the cells towards progenitor-like state, hallmark of CM. The CM development in carney complex also signifies the role of TS in cardiac cells.

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Identification of metabolic pathways underlying FGF1 and CHIR99021-mediated cardioprotection

Cited by 6 publications

References 99 publications

Identification of the metabolic state of surviving cardiomyocytes in the human infarcted heart by spatial single-cell transcriptomics

Identification of the metabolic state of surviving cardiomyocytes in the human infarcted heart by spatial single-cell transcriptomics

Peptide-Guided Nanoparticle Drug Delivery for Cardiomyocytes

The benign nature and rare occurrence of cardiac myxoma as a possible consequence of the limited cardiac proliferative/ regenerative potential: a systematic review

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