Abstract
Endoplasmic reticulum (ER) stress and oxidative stress contribute greatly to myocardial ischemia-reperfusion (MI/R) injury. Naringenin, a flavonoid derived from the citrus genus, exerts cardioprotective effects. However, the effects of naringenin on ER stress as well as oxidative stress under MI/R condition and the detailed mechanisms remain poorly defined. This study investigated the protective effect of naringenin on MI/R-injured heart with a focus on cyclic guanosine monophosphate- (cGMP-) dependent protein kinase (PKG) signaling. Sprague-Dawley rats were treated with naringenin (50 mg/kg/d) and subjected to MI/R surgery with or without KT5823 (2 mg/kg, a selective inhibitor of PKG) cotreatment. Cellular experiment was conducted on H9c2 cardiomyoblasts subjected to simulated ischemia-reperfusion treatment. Before the treatment, the cells were incubated with naringenin (80 μmol/L). PKGIα siRNA was employed to inhibit PKG signaling. Our in vivo and in vitro data showed that naringenin effectively improved heart function while it attenuated myocardial apoptosis and infarction. Furthermore, pretreatment with naringenin suppressed MI/R-induced oxidative stress as well as ER stress as evidenced by decreased superoxide generation, myocardial MDA level, gp91phox expression, and phosphorylation of PERK, IRE1α, and EIF2α as well as reduced ATF6 and CHOP. Importantly, naringenin significantly activated myocardial cGMP-PKGIα signaling while inhibition of PKG signaling with KT5823 (in vivo) or siRNA (in vitro) not only abolished these actions but also blunted naringenin's inhibitory effects against oxidative stress and ER stress. In summary, our study demonstrates that naringenin treatment protects against MI/R injury by reducing oxidative stress and ER stress via cGMP-PKGIα signaling. Its cardioprotective effect deserves further clinical study.
Highlights
Acute myocardial infarction (AMI) remains one of the leading causes of death worldwide
The primary antibodies against caspase-3, cleaved caspase-3, protein kinase RNA-like endoplasmic reticulum kinase (PERK), p-PERK (Thr980), eukaryotic translation initiation factor 2 subunit-α (EIF2α), p-EIF2α (Ser51), vasodilator-stimulated phosphoprotein (VASP), and p-VASP (Ser239) were purchased from Cell Signaling Technology (Danvers, MA, USA)
To examine the influence of naringenin and PKG signaling inhibitor on cardiac damage after myocardial ischemia-reperfusion (MI/R) surgery, we treated the rats with naringenin at a dose of 50 mg/kg/d for 5 days and performed MI/R surgery on them in the presence or absence of KT5823 (2 mg/kg)
Summary
Acute myocardial infarction (AMI) remains one of the leading causes of death worldwide. Restoration of blood flow as soon as possible, named reperfusion, has been established as the major strategy to treat AMI, it can result in remarkable cardiac damage [1]. Despite that efforts have been made to explore the rescue approaches for treating myocardial ischemia-reperfusion (MI/R) injury, further studies are still needed to find the effective therapeutic strategies [2, 3]. MI/R injury is a quite intricate process involving numerous mechanisms. We and others have found that severe ER stress is one of the lethal contributors to cardiomyocyte death under stress conditions [5,6,7,8]
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