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Updated: Oct 25, 2025
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
κ Opioid Receptor Agonist Inhibits Myocardial Injury in Heart Failure Rats through Activating Nrf2/HO-1 Pathway and
Tengfei Wu1, Hui Yao2, Binghua Zhang3
1Department of Laboratory Animal Science, China Medical University, Shenyang, Liaoning 110122, China.
Objectives:
We aimed to observe the protective effect of κ opioid receptor (κ-OR) agonist on myocardial injury in heart failure (HF) rats and its effect on Ca2+-SERCA2a and to explore the regulatory mechanism with the Nrf2/HO-1 signaling pathway.
Methods:
50 Sprague-Dawley rats were randomly divided into the following groups: the sham operation group (sham group), HF model group (HF group), HF+κ-OR agonist U50488 group (HU group), HF+U50488H+novel calmodulin-dependent protein kinase II (CaMKII) agonist (oleic acid) (HUO group), and HF+U50488H+Nrf2 inhibitor (HUM group). The HF rat's model was established through surgical ligation of the left anterior descending coronary artery and the exhausting swimming exercise. After that, rat's cardiac function was monitored by echocardiography. HE and MASSON staining was used to detect the myocardial injury, and TUNEL staining was used to detect the myocardial apoptosis. ELISA was performed to detect the biomarkers of oxidative stress. Moreover, the distribution of reactive oxygen species (ROS) and Nrf2 was detected under immunofluorescence. The expression of sarco/endoplasmic reticulum calcium (Ca2+) ATPase (SERCA) 2a, calmodulin, endoplasmic reticulum stress- (ERS-) related proteins, and Nrf2/HO-1 signaling pathway-related proteins were detected by Western Blotting.
Results:
κ-OR agonist U50488H can significantly enhance rat's cardiac function, reduce the injury and apoptosis of myocardial cells, and alleviate endoplasmic reticulum stress injury in HF rats via upregulating the SERCA2a expression and inhibiting the Ca2+ influx. Furthermore, U50488H could also inhibit the phosphorylation of CaMKII and cAMP-response element binding protein (CREB). Additionally, administration of CaMKII-specific agonist could partially block the therapeutic effect of κ-OR agonist on the myocardium of HF rats. Interestingly, the antagonist of Nrf2 could also significantly reverse the therapeutic effect of κ-OR agonist. Therefore, these results suggested that the effect of U50488H on HF rats is dependent on regulating CaMKII phosphorylation and activating the Nrf2/HO-1 pathway.
Conclusion:
κ-OR agonists U50488H can improve ERS in cardiomyocytes and relieve myocardial injury in HF rats through activating the Nrf2/HO-1 pathway and regulating Ca2+-SERCA2a to inhibit Ca2+ influx.
Insights
The kappa-opioid receptor (κ-OR) agonist U50488H protects against heart failure (HF) by improving cardiac function and reducing myocardial injury. This effect is mediated by regulating Ca2+-SERCA2a and activating the Nrf2/HO-1 pathway.
Area of Science:
- Cardiovascular Biology
- Pharmacology
- Molecular Medicine
Background:
- Heart failure (HF) is a complex syndrome characterized by impaired cardiac function.
- Myocardial injury and endoplasmic reticulum stress (ERS) are key contributors to HF progression.
- Targeting specific receptors and signaling pathways offers potential therapeutic strategies for HF.
Purpose of the Study:
- To investigate the protective effects of a κ-opioid receptor (κ-OR) agonist on myocardial injury in a rat model of heart failure.
- To elucidate the role of Ca2+-SERCA2a regulation and the Nrf2/HO-1 signaling pathway in the observed protective effects.
- To explore the involvement of CaMKII in the therapeutic mechanism of the κ-OR agonist.
Main Methods:
- Establishment of a heart failure (HF) rat model using coronary artery ligation and exhaustive swimming.
- Administration of the κ-OR agonist U50488H, with or without CaMKII or Nrf2 modulators.
- Assessment of cardiac function via echocardiography, myocardial injury/apoptosis through histology and TUNEL staining.
- Measurement of oxidative stress biomarkers, reactive oxygen species (ROS), and protein expression related to Ca2+-SERCA2a and the Nrf2/HO-1 pathway using ELISA and Western Blotting.
Main Results:
- The κ-OR agonist U50488H significantly improved cardiac function and reduced myocardial injury and apoptosis in HF rats.
- U50488H upregulated SERCA2a expression, inhibited Ca2+ influx, and alleviated endoplasmic reticulum stress (ERS).
- The protective effects were partially reversed by a CaMKII agonist and significantly reversed by an Nrf2 antagonist, indicating dependence on these pathways.
Conclusions:
- κ-opioid receptor (κ-OR) agonist U50488H demonstrates significant cardioprotective effects in heart failure (HF).
- The mechanism involves enhancing Ca2+-SERCA2a activity to inhibit Ca2+ influx and alleviating endoplasmic reticulum stress (ERS).
- Activation of the Nrf2/HO-1 pathway and regulation of CaMKII phosphorylation are crucial for the therapeutic benefits of U50488H in HF.
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