Propofol ameliorates hyperglycemia-induced cardiac hypertrophy and dysfunction via heme oxygenase-1/signal transducer and activator of transcription 3 signaling pathway in rats

• Published in: Critical care medicine Vol. 42; no. 8; p. e583
• Main Authors: Xu, Jinjin, Li, Haobo, Irwin, Michael G, Xia, Zhong-Yuan, Mao, Xiaowen, Lei, Shaoqing, Wong, Gordon T, Hung, Victor, Cheung, Chi Wai, Fang, Xiangming, Clanachan, Alexander S, Xia, Zhengyuan
• Format: Journal Article
• Language: English
• Published: United States 01.08.2014
• Subjects: Activating Transcription Factor 3 - drug effects; Animals; Antioxidants - pharmacology; Apoptosis - drug effects; Cardiomegaly - drug therapy; Cardiomegaly - etiology; Cardiomegaly - metabolism; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Type 1 - chemically induced; Diabetes Mellitus, Type 1 - complications; Enzyme Activation; Heme Oxygenase-1 - drug effects; Heme Oxygenase-1 - metabolism; Hyperglycemia - complications; Male; Myocytes, Cardiac - metabolism; Oxidative Stress - drug effects; Propofol - pharmacology; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects
• ISSN: 1530-0293
• DOI: 10.1097/CCM.0000000000000415

Heme oxygenase-1 is inducible in cardiomyocytes in response to stimuli such as oxidative stress and plays critical roles in combating cardiac hypertrophy and injury. Signal transducer and activator of transcription 3 plays a pivotal role in heme oxygenase-1-mediated protection against liver and lung injuries under oxidative stress. We hypothesized that propofol, an anesthetic with antioxidant capacity, may attenuate hyperglycemia-induced oxidative stress in cardiomyocytes via enhancing heme oxygenase-1 activation and ameliorate hyperglycemia-induced cardiac hypertrophy and apoptosis via heme oxygenase-1/signal transducer and activator of transcription 3 signaling and improve cardiac function in diabetes. Treatment study. Research laboratory. Sprague-Dawley rats. In vivo and in vitro treatments. At 8 weeks of streptozotocin-induced type 1 diabetes in rats, myocardial 15-F2t-isoprostane was significantly increased, accompanied by cardiomyocyte hypertrophy and apoptosis and impaired left ventricular function that was coincident with reduced heme oxygenase-1 activity and signal transducer and activator of transcription 3 activation despite an increase in heme oxygenase-1 protein expression as compared to control. Propofol infusion (900 μg/kg/min) for 45 minutes significantly improved cardiac function with concomitantly enhanced heme oxygenase-1 activity and signal transducer and activator of transcription activation. Similar to the changes seen in diabetic rat hearts, high glucose (25 mmol/L) exposure for 48 hours led to cardiomyocyte hypertrophy and apoptosis, both in primary cultured neonatal rat cardiomyocytes and in H9c2 cells compared to normal glucose (5.5 mmol/L). Hypertrophy was accompanied by increased reactive oxygen species and malondialdehyde production and caspase-3 activity. Propofol, similar to the heme oxygenase-1 inducer cobalt protoporphyrin, significantly increased cardiomyocyte heme oxygenase-1 and p-signal transducer and activator of transcription protein expression and heme oxygenase-1 activity and attenuated high-glucose-mediated cardiomyocyte hypertrophy and apoptosis and reduced reactive oxygen species and malondialdehyde production (p < 0.05). These protective effects of propofol were abolished by heme oxygenase-1 inhibition with zinc protoporphyrin and by heme oxygenase-1 or signal transducer and activator of transcription 3 gene knockdown. Heme oxygenase-1/signal transducer and activator of transcription 3 signaling plays a critical role in propofol-mediated amelioration of hyperglycemia-induced cardiomyocyte hypertrophy and apoptosis, whereby propofol improves cardiac function in diabetic rats.