Abstract
Bisoprolol (B) exerts potential cardioprotective effects against myocardial ischemia/reperfusion (I/R) injury. Unfolded protein response (UPR) attenuates I/R injury induced apoptosis by reducing oxidative damage and inflammation response. The current study investigated whether the protective effects of bisoprolol resulted from modulating UPR and anti-inflammatory during myocardial I/R condition and elucidated its potential mechanisms. Sprague-Dawley rats were treated with B in the absence or presence of the injected UPR activator dithiothreitol (DTT) and then subjected to myocardial I/R surgery. In vitro, cultured H9C2 cells were pretreated with B or DTT and then subjected to simulate ischemia reperfusion (SIR) operation. Bisoprolol conferred cardioprotective effects by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase levels, suppressing TNF-α and IL-6 secretion, inhibiting UPR signal pathways and downregulating caspase-12 and caspase-3 expressions. Consistently, B conferred similar antioxidative and anti-inflammatory effects against SIR injury in cultured H9C2 cardiomyocytes. Pretreatment with DTT or C/EBP homologous protein (CHOP) overexpression mediated by lentivirus administration both abolished these effects. In summary, our results demonstrate that Bisoprolol protects myocardium cells against ischemia/reperfusion injury partly by attenuating unfolded protein response.
Highlights
Ischemic heart disease including acute coronary syndrome remains the leading cause of mortality and disability worldwide[1]
The C/EBP homologous protein (CHOP) and caspase-12 were involved in endoplasmic reticulum (ER) stress-induced apoptosis, which were confirmed in many studies[9,10,11]
Activated inositol requiring enzyme 1 (IRE1) pathway splices the mRNA of a transcription factor called X-box-binding protein-1 (XBP1), removing a 26-bp nucleotide intron from the full-length XBP1 mRNA that creates a translational frame shift leading to the expression of a spliced XBP115,16
Summary
Ischemic heart disease including acute coronary syndrome remains the leading cause of mortality and disability worldwide[1]. UPR is characterized by the activation of three ER transmembrane effector proteins: transcription factor-6 (ATF-6), inositol requiring enzyme 1 (IRE1), and PKR-like ER kinase (PERK)[13], which mediated three branches signal pathway of UPR. Activated IRE1 pathway splices the mRNA of a transcription factor called X-box-binding protein-1 (XBP1), removing a 26-bp nucleotide intron from the full-length XBP1 mRNA that creates a translational frame shift leading to the expression of a spliced XBP1 (sXPB1)[15,16]. Activated PERK phosphorylates eukaryotic translation initiation factor 2 subunit α (eIF2α), which leads to inhibition of global protein synthesis[17]. When ER stress is excessive and/or prolonged, apoptotic signals are initiated by the UPR in the ER, including induction of CHOP, activation of Jun N-terminal kinase (JNK), and cleavage of caspase-1219–21. The underlying molecular mechanism(s) responsible for this effect remains unidentified
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