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The activated caveolin-3/μ-opioid receptor complex drives morphine-induced rescue therapy in failing hearts

Chengxiao Guo1,2, Xinxin Pan1,2, Mengyun Dou1,2

  • 1Department of Anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.

British Journal of Pharmacology
|October 20, 2024
PubMed
Abstract

Insights

Morphine protects failing hearts from ischemia/reperfusion injury by interacting with caveolin-3 (Cav3) and μ opioid receptors. This Cav3-μ receptor complex targets the ERK1/2 pathway, offering a new therapeutic strategy for heart failure.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Pharmacology

Background:

  • Opioid analgesics can mitigate ischemia/reperfusion (I/R) injury in chronic heart failure.
  • The precise mechanisms and molecular targets underlying opioid-induced cardioprotection remain largely unknown.
  • This study investigates the role of caveolin-3 (Cav3) and its interaction with μ opioid receptors in morphine's protective effects on failing hearts.

Purpose of the Study:

  • To determine if caveolin-3 (Cav3) interacts with μ opioid receptors.
  • To investigate the role of Cav3-μ receptor interactions in morphine-induced cardioprotection in failing hearts.
  • To explore the therapeutic potential of the Cav3-μ receptor complex in heart failure.

Main Methods:

  • Western blot, immunofluorescence, and co-immunoprecipitation were used to assess Cav3 and μ receptor protein levels and localization in human and rat heart tissues.
  • Caveolae were disrupted using methyl-β-cyclodextrin (MβCD) or AAV-Cav3 shRNA in failing rat hearts.
  • Myocardial I/R injury models in perfused failing rat hearts were used to evaluate the effects of μ opioid receptor antagonist CTOP and morphine preconditioning.

Main Results:

  • Cav3 and μ receptor protein levels were elevated in failing hearts compared to controls, correlating positively with disease severity.
  • Cardiac Cav3 protein signals colocalized with μ receptors in both human and rat heart sections.
  • Disrupting caveolae or reducing Cav3 expression inhibited morphine-induced ERK1/2 phosphorylation and cardioprotection; CTOP administration reduced Cav3 expression and morphine's protective effects.

Conclusions:

  • Up-regulation of the Cav3/μ receptor complex is crucial for morphine's protection against I/R injury in failing hearts, mediated via the ERK1/2 pathway.
  • The activated Cav3/μ receptor complex represents a novel therapeutic target for opioid-based treatments in heart failure.
  • Targeting the Cav3/μ receptor complex may offer a new strategy to combat ischemic insults in patients with heart failure.
Keywords:
caveolin‐3chronic heart failureischaemia/reperfusion injurymorphineμ‐opioid receptor

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