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

Abstract

OBJECTIVES:

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.

DESIGN:

Treatment study.

SETTING:

Research laboratory.

SUBJECTS:

Sprague-Dawley rats.

INTERVENTIONS:

In vivo and in vitro treatments.

MEASUREMENTS AND MAIN RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Jinjin Xu, Haobo Li, Michael G Irwin, Zhong-Yuan Xia, Xiaowen Mao, Shaoqing Lei, Gordon T Wong, Victor Hung, Chi Wai Cheung, Xiangming Fang, Alexander S Clanachan, Zhengyuan Xia
• Journal: Critical care medicine (Crit Care Med) Vol. 42 Issue 8 Pg. e583-94 (Aug 2014) ISSN: 1530-0293 [Electronic] United States
• PMID: 24810525 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Activating Transcription Factor 3
• Antioxidants
• Reactive Oxygen Species
• Heme Oxygenase-1
• Propofol

Topics

• Activating Transcription Factor 3 (drug effects)
• Animals
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Cardiomegaly (drug therapy, etiology, metabolism)
• Diabetes Mellitus, Experimental (complications)
• Diabetes Mellitus, Type 1 (chemically induced, complications)
• Enzyme Activation
• Heme Oxygenase-1 (drug effects, 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)