Hydromorphone hydrochloride preconditioning combined with postconditioning attenuates myocardial ischemia/reperfusion injury in rats by improving mitochondrial function and activating the PI3K/Akt signaling pathway

Abstract

Abstract Background Therapeutic methods such as thrombolytic therapy or percutaneous coronary intervention (PCI) can quickly restore blood flow in myocardial ischemic area. Thanks to these therapeutic methods, the death risk of acute myocardial infarction (AMI) has been reduced significantly. However, these therapeutic strategies may also cause myocardial ischemia/reperfusion injury (MIRI) and poor prognosis of patients. Previous studies have revealed protective effect of the opioid drug hydromorphone hydrochloride (HH) on brain ischemia/reperfusion injury (IRI) in rats and mice. However, there are few studies on the effect of HH on MIRI. Therefore, this study was designed to explore the protective effect and potential mechanism of HH on MIRI. Methods Except Sham group, MIRI models were established by ligating and relaxing the left anterior descending coronary artery, and HH (0.3μmol/L) was injected through the tail vein 10 min before ligation (HH-pre group), 10 min after reperfusion (HH-post group) and twice at the above two time points (HH-pre+post group). After intervention, the cardiac function of rats was evaluated by echocardiography, and the serum of rats was collected for the detection of levels of myocardial injury markers. Next, the area of myocardial infarction was evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining, followed by the measurement of levels of malondialdehyde (MDA), superoxide dismutase (SOD), lactate dehydrogenase (LDH), reactive oxygen species (ROS) and adenosine triphosphate (ATP). Besides, the relative content of mitochondrial DNA (mtDNA) was detected by qRT-PCR; mitochondrial biogenesis and phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt)signaling pathway were evaluated by western blot. Results Compared with the I/R group, rats in the HH-pre group, HH-post group and HH-pre+post group exhibited improved cardiac function, decreased myocardial infarction area, reduced serum myocardial injury markers, alleviated oxidative stress, improved mitochondrial function, up-regulated mitochondrial biogenesis and activated PI3K/Akt signaling pathway. Moreover, the HH-pre+post group was superior to the HH-pre group or the HH-post group in the above aspects. Conclusion: HH has protective effect on MIRI. HH preconditioning combined with postconditioning shows optimal efficacy, and such efficacy may be achieved by promoting mitochondrial biogenesis to improve mitochondrial function and reduce oxidative stress, and activating the PI3K/Akt signaling pathway.