BACKGROUND: Myocardial ischemia-reperfusion injury is a main cause of postoperative cardiac dysfunction, and a burst of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and interleukin 8, plays a pivotal role. Recently, JTE-607 has been reported as a potent inhibitor of the multiple inflammatory cytokines in the endotoxin shock mouse model. In this study we proved the hypothesis that JTE-607 might attenuate myocardial ischemia-reperfusion injury in a rat model. METHODS: The isolated rat hearts in the JTE-607 preconditioning group (J group, n = 8) or control group (C group, n = 8) were subjected to warm ischemia (37 degrees C) for 30 minutes, followed by 60 minutes of reperfusion with the Langendorff perfusion system. RESULTS: Left ventricular developed pressure and maximum dp/dt after reperfusion were significantly improved in the J group than in the C group (P <.01). Creatine phosphokinase leakage is significantly lower in the J group (P <.05). Moreover, the tissue cytokine levels, such as tumor necrosis factor alpha, interleukin 6, and interleukin 8, in the myocardium were significantly lower in the J group than in the C group (P <.05). CONCLUSION: These results suggested that the pharmacologic preconditioning of JTE-607 inhibits a burst of endogenous cytokines in the myocardium, resulting in the improvement of cardiac function after ischemia-reperfusion injury. Thus JTE-607 might be a novel therapeutic strategy for the protection of postoperative cardiac dysfunction in cardiac surgery.
BACKGROUND:Myocardial ischemia-reperfusion injury is a main cause of postoperative cardiac dysfunction, and a burst of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and interleukin 8, plays a pivotal role. Recently, JTE-607 has been reported as a potent inhibitor of the multiple inflammatory cytokines in the endotoxin shock mouse model. In this study we proved the hypothesis that JTE-607 might attenuate myocardial ischemia-reperfusion injury in a rat model. METHODS: The isolated rat hearts in the JTE-607 preconditioning group (J group, n = 8) or control group (C group, n = 8) were subjected to warm ischemia (37 degrees C) for 30 minutes, followed by 60 minutes of reperfusion with the Langendorff perfusion system. RESULTS:Left ventricular developed pressure and maximum dp/dt after reperfusion were significantly improved in the J group than in the C group (P <.01). Creatine phosphokinase leakage is significantly lower in the J group (P <.05). Moreover, the tissue cytokine levels, such as tumor necrosis factor alpha, interleukin 6, and interleukin 8, in the myocardium were significantly lower in the J group than in the C group (P <.05). CONCLUSION: These results suggested that the pharmacologic preconditioning of JTE-607 inhibits a burst of endogenous cytokines in the myocardium, resulting in the improvement of cardiac function after ischemia-reperfusion injury. Thus JTE-607 might be a novel therapeutic strategy for the protection of postoperative cardiac dysfunction in cardiac surgery.
Authors: Nathan T Ross; Felix Lohmann; Rohan E J Beckwith; Seth Carbonneau; Aleem Fazal; Wilhelm A Weihofen; Scott Gleim; Michael Salcius; Frederic Sigoillot; Martin Henault; Sarah H Carl; Juan B Rodríguez-Molina; Howard R Miller; Scott M Brittain; Jason Murphy; Mark Zambrowski; Geoffrey Boynton; Yuan Wang; Aye Chen; Gregory J Molind; Johannes H Wilbertz; Caroline G Artus-Revel; Min Jia; Favour A Akinjiyan; Jonathan Turner; Judith Knehr; Walter Carbone; Sven Schuierer; John S Reece-Hoyes; Kevin Xie; Chitra Saran; Eric T Williams; Guglielmo Roma; Matt Spencer; Jeremy Jenkins; Elizabeth L George; Jason R Thomas; Gregory Michaud; Markus Schirle; John Tallarico; Lori A Passmore; Jeffrey A Chao Journal: Nat Chem Biol Date: 2019-12-09 Impact factor: 15.040