Dataset Information

The role HINT2 in DOX-induced cardiac damage

ABSTRACT: This file include 9 sample: heart sample from WT mice (1, 2, 3)+heart sample from WT mice treated with DOX (4,5,6)+heart sample from HINT2 cKO mice treated with DOX (7,8,9))

ORGANISM(S): Mus Musculus

SUBMITTER: Aijun Sun

PROVIDER: PXD056142 | iProX | Wed Sep 18 00:00:00 BST 2024

REPOSITORIES: iProX

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Publications

Histidine triad nucleotide-binding protein 2 attenuates doxorubicin-induced cardiotoxicity through restoring lysosomal function and promoting autophagy in mice.

Jiang Hao H Zhang Jinyan J Jia Daile D Liu Liwei L Gao Jinfeng J Zhang Beijian B Dong Zhen Z Sun Xiaolei X Yang Wenlong W Ou Tiantong T Ding Suling S He Luna L Shi Yiqin Y Hu Kai K Sun Aijun A Ge Junbo J

MedComm 20250217 3

Doxorubicin (DOX) is an effective chemotherapy drug widely used against various cancers but is limited by severe cardiotoxicity. Mitochondria-lysosome interactions are crucial for cellular homeostasis. This study investigates the role of histidine triad nucleotide-binding protein 2 (HINT2) in DOX-induced cardiotoxicity (DIC). We found that HINT2 expression was significantly upregulated in the hearts of DOX-treated mice. Cardiac-specific <i>Hint2</i> knockout mice exhibited significantly worse ca ...[more]

PMID: 39968501

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Project description:Rationale: The Id1 and Id3 genes play major roles during cardiac development, despite their expression being confined to non-myocardial layers (endocardium â?? endothelium - epicardium). We previously described that Id1â??/â??Id3â??/â?? double knockout (dKO) mouse embryos die at mid-gestation from multiple cardiac defects, but early demise precluded the studies of the roles of Id in the adult mice. Objective: To elucidate postnatal roles of Id genes in the heart. Methods and Results: We ablated Id1 gene in the vasculature and Id3 gene globally to generate Tie2Cre+Id1F/â??Id3â??/â?? and Tie2Cre+Id1F/FId3â??/â?? conditional KO (Id cKO) embryos. Half of the Id cKO mice die at birth. Postnatal demise was associated with cardiac underdevelopment, enlargement, muscular ventricular septal and endothelial defects. Surviving Id cKO mice exhibited dilated, fibrotic cardiomyopathy associated with defects in the vasculature. The adult cardiac phenotype progressed into heart failure and resembled endomyocardial fibroelastosis. An abnormal vascular response was also observed in the healing process of excisional skin wounds of Id cKO mice. Expression patterns of vascular, fibrotic and hypertrophic markers were altered in the Id cKO hearts, but addition of Insulin-Like Growth Factor binding protein-3 (IGFbp3) reversed gene expression profiles of vascular and fibrotic, but not hypertrophic markers. Conclusions: Conditional ablation of Id genes in the vasculature leads to dilated fibrotic cardiomyopathy. The findings could reveal important insights into the role(s) of the endocardial network of the endothelial lineage to the development of dilated fibrotic cardiomyopathy and identify a potential therapeutic target, IGFbp3, in its treatment. Total RNA from heart tissue was isolated (RNeasy, QIAGEN) from P180 WT, Id control, Id cKO, IGFbp3 incubated Id cKO, and control incubated Id cKO. RNA was converted to cDNA, cRNA, and hybridized to DNA sequences contained in the GeneChip Mouse Gene 1.0 ST Array (Affymetrix). Information from at least duplicate samples was compared and filtered by fold change >2 (Id cKO vs WT, Id control vs WT, IGFbp3 incubated Id cKO vs. control incubated Id cKO) and statistical p-value<0.001.

Project description:Purpose: Next-generation sequencing (NGS) provides the change of cellular pathways at the transcriptomic level. The overall goal for this research are to compare the transcriptome profiling by NGS in cardiomyocyte-specific FAM210A conditional knockout (cKO) hearts and control (Ctrl) hearts at two different time points and to evaluate the signaling pathways affected by FAM210A deficiency in the heart at the molecular level. Methods: Cardiac mRNA profiles of FAM210A cKO and Ctrl hearts were generated by deep sequencing in triplicate at the late stage (~10 weeks post Fam210a cKO by tamoxifen induction) and in quadruplicates at the early stage (~5 weeks post Fam210a cKO by tamoxifen induction). Results: Using an optimized data analysis workflow from the Genomic Research Center at the University of Rochester, we mapped ~30 millian sequence reads per sample to the mouse genome in the hearts of Ctrl and Fam210a cKO mice at both early and late stages. RNA-seq data comfirmed the knockout of FAM210A in the Fam210a cKO hearts. We identified differentially expressed genes at both early and late stages of FAM210A cKO heart compared with Ctrl hearts (adjust P valuse <0.05). Among upregulated genes, we observed enhanced integrated stress response (ISR) gene signature at both early and late stages in Fam210a cKO hearts compared with Ctrl hearts, including aminoacyl-tRNA synthetases, amino acid synthases, and one-carbon metabolic enzymes. The downregulated genes were not common between the two stages. At the early stage, the top enriched pathways include negative regulation of blood coagulation and wound healing and fatty acid metabolic process. In contrast, at the late stage, the major pathways include sulfide oxidation, glucose import, and mitochondrial ETC complex assembly. Conclusions: Our study provides the first detailed transcriptomic anslysis of cardiomyocyte specific knockout of Fam210a in the heart at two different time-points by NGS. The RNA-seq data reported here provide a framework for comparative investigation of expression profiles in the hearts of FAM210A cKO compared with Ctrl hearts. Based on our analysis, we conclude that ISR is persistently activated in Fam210a cKO hearts, which may be a pro-survival compensatory response caused by the dysfunction of mitochondria in Fam210a cKO hearts. ISR activation can reprogram global cap-dependent translation and cellular metabolism simultaneously.

Dataset Information

The role HINT2 in DOX-induced cardiac damage

Publications

Histidine triad nucleotide-binding protein 2 attenuates doxorubicin-induced cardiotoxicity through restoring lysosomal function and promoting autophagy in mice.

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