Abstract
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.
Highlights
Heart failure (HF) is caused by structural or functional abnormality of the heart, leading to impaired cardiac blood circulation, reduced cardiac function, and failure to meet the metabolic needs of the body [1]
The results showed that reactive oxygen species (ROS) was accumulated as HF occurs in rats (Figure 2(a)); κ opioid receptor (κ-OR) agonist U50488H can inhibit the release of ROS, reduce MDA contents in plasma, and promote the release of superoxide dismutase (SOD) and CAT (Figure 2(b))
HF is characterized by weakened myocardial contractility and/or diastolic dysfunction and reduced cardiac output, which cannot satisfy the demands of tissue and cell metabolisms [1]
Summary
Heart failure (HF) is caused by structural or functional abnormality of the heart, leading to impaired cardiac blood circulation, reduced cardiac function, and failure to meet the metabolic needs of the body [1]. The homeostasis of ER could be Oxidative Medicine and Cellular Longevity broken with the occurrence of ischemia [5], hypoxia [6], lipid overload [7], viral infection [8], and drugs/toxin effect [9], leading to the accumulation of folding or unfolding protein in the cavity or the imbalance state of Ca2+ in the ER, called endoplasmic reticulum stress (ERS) [10, 11]. The sarcoplasmic/endoplasmic reticulum Ca2+ ATPase-2a (SERCA2a) regulates the contractile and diastolic functions of myocardial cells via participating in the transport of Ca2+ and maintains the steady state of Ca2+ [13]. Decreased SERCA2a during ERS can cause the imbalance of Ca2+ homeostasis in myocardial cells, which induces cardiac contractile dysfunction leading to HF [14]
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