Propofol Ameliorates Hyperglycemia-Induced Cardiac Hypertrophy and Dysfunction via Heme Oxygenase-1/Signal Transducer and Activator of Transcription 3 Signaling Pathway in Rats
Propofol Ameliorates Hyperglycemia-Induced Cardiac Hypertrophy and Dysfunction via Heme Oxygenase-1/Signal Transducer and Activator of Transcription 3 Signaling Pathway in Rats
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DOI：
10.1097/ccm.0000000000000415
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发表时间：
2014-08-01
影响因子：
8.8
通讯作者：
Xia, Zhengyuan
中科院分区：
文献类型：
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作者：
Xu, Jinjin;Li, Haobo;Xia, Zhengyuan
目的：血红素氧合酶-1在心肌细胞中响应于刺激如氧化应激是可诱导的，并且在对抗心脏肥大和损伤中起关键作用。信号转导和转录激活因子3在血红素加氧酶1介导的抗氧化应激下肝和肺损伤中起关键作用。我们假设，异丙酚，一种具有抗氧化能力的麻醉剂，可以通过增强血红素加氧酶-1激活来减弱高血糖诱导的心肌细胞氧化应激，通过血红素加氧酶-1/信号转导子和转录激活子3信号转导来改善高血糖诱导的心肌肥大和凋亡，并改善糖尿病患者的心功能。主题：Sprague-Dawley大鼠。干预措施：体内和体外治疗。测量和主要结果：在链脲佐菌素诱导的1型糖尿病大鼠8周时，心肌15-F-2t-异前列腺素显著增加，伴随着心肌细胞肥大和凋亡以及左心室功能受损，这与血红素加氧酶-1活性降低以及信号转导和转录激活因子3激活一致，尽管血红素加氧酶-1活性增加，1蛋白表达与对照相比。丙泊酚输注（900 g/kg/min）45分钟显著改善心功能，同时增强血红素加氧酶-1活性和信号转导子和转录激活子的激活。与糖尿病大鼠心脏中观察到的变化相似，与正常葡萄糖（5.5 mmol/L）相比，高葡萄糖（25 mmol/L）暴露48小时导致原代培养的新生大鼠心肌细胞和H9c2细胞中的心肌细胞肥大和凋亡。肥大伴随着活性氧和丙二醛的产生和caspase-3活性的增加。丙泊酚与血红素加氧酶-1诱导剂钴原卟啉相似，显著增加心肌细胞血红素加氧酶-1和p-信号转导子和转录激活子蛋白表达以及血红素加氧酶-1活性，减轻高糖介导的心肌细胞肥大和凋亡，减少活性氧和丙二醛产生（p <0.05）。异丙酚的这些保护作用被锌原卟啉抑制血红素氧合酶-1和血红素氧合酶-1或信号转导和转录激活因子3基因敲低所消除。血红素氧合酶-1/信号转导和转录激活因子3信号转导在丙泊酚介导的高血糖诱导的心肌细胞肥大和凋亡的改善中起关键作用，由此丙泊酚改善糖尿病大鼠的心脏功能。
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 oxygenase1-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-F-2t-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 g/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 propofolmediated amelioration of hyperglycemia-induced cardiomyocyte hypertrophy and apoptosis, whereby propofol improves cardiac function in diabetic rats.