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Gefapixant, a Novel P2X3 Antagonist, Protects against Post Myocardial Infarction Cardiac Dysfunction and Remodeling Via Suppressing NLRP3 Inflammasome

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Abstract

Objective

The ATP responsive P2 purinergic receptors can be subdivided into metabotropic P2X family and ionotropic P2Y family. Among these, P2X3 is a type of P2X receptor which is specifically expressed on nerves, especially on pre-ganglionic sensory fibers. This study investigates whether gefapixant possesses the potential of inhibiting cardiac sympathetic hypersensitivity to protect against cardiac remodeling in the context of myocardial infarction.

Methods

The Sprague-Dawley rats were divided randomly into three groups: sham group-myocardial infarction group, and myocardial infarction with gefapixant treatment group. Myocardial infarction was induced by left anterior descending branch ligation. The gefapixant solution was intraperitoneally injected each time per day for 7 days and the appropriate dosage of gefapixant was determined according to the results of hematoxylin-eosin (HE) staining and myocardial injury biomarkers. Conditions of cardiac function were assessed by echocardiograph and cardiac fibrosis was evaluated by Western blotting and immunofluorescence staining of collagen I and collagen III. The sympathetic innervation was detected by norepinephrine concentration (pg/mL), in-vivo electrophysiology, and typical sympathetic biomarkers. Inflammatory cell infiltration was shown from immunofluorescence staining and pro-inflammatory signaling pathway activation was checked by immunohistology, quantitative realtime PCR (qPCR) and Western blotting.

Results

It was found that gefapixant injection of 10 mg/kg per day had the highest dosage-efficacy ratio. Furthermore, gefapixant treatment improved cardiac pump function as shown by increased LVEF and LVFS, and decreased LVIDd and LVIDs. The expression levels of collagen I and collagen III, and TNF-α were all decreased by P2X3 inhibition. Mechanistically, the decreased activation of nucleotide-binding and oligomerization domain-like receptors family pyrin-domain-containing 3 (NLRP3) inflammasome and subsequent cleavage of caspase-1 which modulated interleukin-1β (IL-1β) and IL-18 level in heart after gefapixant treatment were associated with the suppressed cardiac inflammation.

Conclusion

It is suggested that P2X3 inhibition by gefapixant ameliorates post-infarct autonomic nervous imbalance, cardiac dysfunction, and remodeling possibly via inactivating NLRP3 inflammasome.

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Authors and Affiliations

  1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Yan-zhao Wei, Shuang Yang & Yan-hong Tang

  2. Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China

    Yan-zhao Wei, Shuang Yang & Yan-hong Tang

  3. Hubei Key Laboratory of Cardiology, Wuhan, 430060, China

    Yan-zhao Wei, Shuang Yang & Yan-hong Tang

  4. Department of Cardiology, Wuhan No. 1 Hospital, Wuhan Hospital of Traditional Chinese and Western Medicine, Wuhan, 430022, China

    Wei Li

Authors
  1. Yan-zhao Wei
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  2. Shuang Yang
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Corresponding authors

Correspondence to Wei Li or Yan-hong Tang.

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All the authors of the article report no conflicts of interest in this work.

Additional information

This work was supported by the National Natural Science Foundation of China (No. 81370282).

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Wei, Yz., Yang, S., Li, W. et al. Gefapixant, a Novel P2X3 Antagonist, Protects against Post Myocardial Infarction Cardiac Dysfunction and Remodeling Via Suppressing NLRP3 Inflammasome. CURR MED SCI 43, 58–68 (2023). https://doi.org/10.1007/s11596-022-2658-5

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  • DOI: https://doi.org/10.1007/s11596-022-2658-5

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