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Multi-omic map revealed PPARα activation protecting against myocardial ischemia/reperfusion injury by maintaining cardiac metabolic homeostasis [snRNA-seq]

ABSTRACT: The rats were subjected to left anterior descending (LAD) coronary artery ligation for 1 hour, 6 hours (MI1h and MI6h) and 24 hours (MI24h) along with Sham controls (Sham), and 1-hour, 6-hour ischemia followed by reperfusion (MI1h/R and MI6h/R, mimicking early time reperfusion (ETR) and late time reperfusion (LTR), respectively) followed by heart tissue collection 24 hours post MI to mimic the MI/R injury in AMI patients.The heart infarct zones (Sham, MI1h/R, MI6h/R and MI24h) were isolated to single-nucleus transcriptome analysis. Collected nuclei for each sample were loaded onto 10X Chrominum platform. We obtained 22,234 cells and 17,003 genes. Five major cell types were identified, which included cardiomyocytes (CMs), endothelial cells (ECs), fibroblasts (FBs), macrophages (MACs) and smooth muscle cells (SMCs).

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE240848 | GEO | 2024/08/01

REPOSITORIES: GEO

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Project description:Toxoplasma gondii uracil phosphoribosyltransferase (UPRT) converts 4-thiouracil (4TUc) into 4-thiouridine (4TUd), which is incorporated into nascent RNAs and can be biotinylated, then labeled with streptavidin conjugates or isolated via streptavidin-affinity methods. Here, we generated mice that expressed T. gondii UPRT only in cardiomyocytes (CMUPRT mice) and tested our hypothesis that CM-derived miRNAs (CMmiRs) are transferred into remote organs after myocardial infarction (MI) by small extracellular vesicles (sEV) that are released from the heart into the peripheral blood (PBsEV). We found that 4TUd was incorporated with high specificity and sensitivity into RNAs isolated from the hearts and PBsEV of CMUPRT mice six hours after 4TUc injection. In PBsEV, 4TUd was incorporated into CM-specific/enriched miRs including miR-208a, but not into miRs with other organ or tissue-type specificities. 4TUd-labeled miR208a was also present in lung tissues, especially lung endothelial cells (ECs), and CM-derived miR-208a (CMmiR-208a) levels peaked 12 hours after experimentally induced MI in PBsEV and 24 hours after MI in the lung. Notably, miR-208a is expressed from intron 29 of alpha myosin heavy chain (a-MHC), but a-MHC transcripts were nearly undetectable in the lung. When PBsEV from mice that underwent MI (MI-PBsEV) or sham surgery (Sham-PBsEV) were injected into intact mice, the expression of Tmbim6 and NLK, which are suppressed by miR-208a and cooperatively regulate inflammation via the NF-kappa B pathway, was lower in the lungs of MI-PBsEV-treated animals than the lungs of animals treated with Sham-PBsEV or saline. In MI mice, Tmbim6 and NLK were downregulated, whereas endothelial adhesion molecules and pro-inflammatory cells were upregulated in the lung; these changes were significantly attenuated when the mice were treated with miR-208a antagomirs prior to MI surgery. Thus, CMUPRT mice enables us to track sEV-mediated transport of CMmiRs and identify an miR-208a-mediated mechanism by which myocardial injury alters the expression of genes and inflammatory response in the lung.

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Multi-omic map revealed PPARα activation protecting against myocardial ischemia/reperfusion injury by maintaining cardiac metabolic homeostasis [snRNA-seq]

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