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Dual-omics reveals temporal differences in acute sympathetic stress-induced cardiac inflammation following α1 and β-adrenergic receptors activation

Abstract

Sympathetic stress is prevalent in cardiovascular diseases. Sympathetic overactivation under strong acute stresses triggers acute cardiovascular events including myocardial infarction (MI), sudden cardiac death, and stress cardiomyopathy. α1-ARs and β-ARs, two dominant subtypes of adrenergic receptors in the heart, play a significant role in the physiological and pathologic regulation of these processes. However, little is known about the functional similarities and differences between α1- and β-ARs activated temporal responses in stress-induced cardiac pathology. In this work, we systematically compared the cardiac temporal genome-wide profiles of acute α1-AR and β-AR activation in the mice model by integrating transcriptome and proteome. We found that α1- and β-AR activations induced sustained and transient inflammatory gene expression, respectively. Particularly, the overactivation of α1-AR but not β-AR led to neutrophil infiltration at one day, which was closely associated with the up-regulation of chemokines, activation of NF-κB pathway, and sustained inflammatory response. Furthermore, there are more metabolic disorders under α1-AR overactivation compared with β-AR overactivation. These findings provide a new therapeutic strategy that, besides using β-blocker as soon as possible, blocking α1-AR within one day should also be considered in the treatment of acute stress-associated cardiovascular diseases.

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Fig. 1: The differences in transcriptional expression patterns between β-AR agonist (ISO) and α1-AR agonist (PE) treatment.
Fig. 2: Functional enrichment analysis of differentially expressed genes in time series after ISO and PE treatment.
Fig. 3: Differences between the inflammatory cell infiltration induced by ISO and PE.
Fig. 4: Expression analysis of genes associated with neutrophils after ISO and PE treatment.
Fig. 5: PE treatment activates the NF-κB pathway.
Fig. 6: Inhibition of NF-κB significantly reduced inflammatory response after PE treatment.
Fig. 7: Combined analysis of transcriptome and proteome after ISO and PE treatment.
Fig. 8: PE causes metabolic pathway downregulation.
Fig. 9: Illustration of the differences in inflammatory responses between α1-AR and β-AR activation.

Data availability

The RNA-seq data are available in the GEO database with accession number GSE211134. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [67] partner repository with the dataset identifier PXD036011.

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Acknowledgements

This work was supported by the Beijing Municipal Natural Science Foundation [grant number 7191013 to EDD], the National Key R&D Program of China [2021YFF0501401 to HX; 2021YFF1200500 to ZYL], the National Natural Science Foundation of China [grant numbers 82030072, 81822003 to HX; 81830009 to YYZ; 82100280 to JMW], the Haihe Laboratory of Cell Ecosystem Innovation Fund [grant number HH22KYZX0047 to EDD], and the Key Clinical Projects of Peking University Third Hospital [grant number BYSYZD2019022 to HX]. This work was partly supported by grants from Peking-Tsinghua Center for Life Sciences.

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HX and JMW conceived and designed the research; MMZ, DZ, and JMW performed the research; DZ performed the data curation and formal analysis; RW and YBX helped with the experiments; GX and JQS helped with the data analysis; DZ, JMW, HX, and ZYL wrote and edited the manuscript; HX, ZYL, YYZ, and EDD supervised the Project. All authors approved the manuscript.

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Correspondence to Er-dan Dong, Zhi-yuan Li or Han Xiao.

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Zhang, D., Zhao, Mm., Wu, Jm. et al. Dual-omics reveals temporal differences in acute sympathetic stress-induced cardiac inflammation following α1 and β-adrenergic receptors activation. Acta Pharmacol Sin (2023). https://doi.org/10.1038/s41401-022-01048-5

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Keywords

  • adrenergic receptors
  • transcriptomics
  • proteomics
  • acute sympathetic stress
  • cardiac inflammation

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