胃饥饿素和去辛酰基胃饥饿素对异丙肾上腺素诱导的大鼠心肌损伤的心脏保护作用。
Cardioprotective effects of ghrelin and des-octanoyl ghrelin on myocardial injury induced by isoproterenol in rats.
作者信息
Li Lian, Zhang Li-Ke, Pang Yong-Zheng, Pan Chun-Shui, Qi Yong-Fen, Chen Li, Wang Xian, Tang Chao-Shu, Zhang Jing
机构信息
Institute of Cardiovascular Research, Peking University First Hospital, Beijing 100034, China.
出版信息
Acta Pharmacol Sin. 2006 May;27(5):527-35. doi: 10.1111/j.1745-7254.2006.00319.x.
AIM
To determine the cardioprotective action of ghrelin and des-octanoyl ghrelin in rats with isoproterenol-induced myocardial injury.
METHODS
Rats were subcutaneously injected with isoproterenol (ISO; 20, 10, and 5 mg/kg) on d 1, 2 and 3, respectively, and then 3 mg/kg for the next 7 d with or without ghrelin or des-octanoyl-ghrelin (100 microg/kg, twice daily). Plasma ghrelin and growth hormone levels were assayed using radioimmunoassay methods. Growth hormone secretagogue receptor (GHSR) and ghrelin mRNA were determined using RT-PCR. The maximal binding capacity and the affinity for [3H]ghrelin were determined by receptor binding assays.
RESULTS
Compared with controls, ISO-treated rats showed severe myocardial injury, cardiomegaly, infarction-like necrosis and massive fibrosis with increases in irradiated-ghrelin (ir-ghrelin) content in plasma by 67% and myocardia by 66% and in the mRNA level in the myocardia by 93% (P<0.01). ISO-treated rats had 95% (P<0.01) higher GHSR mRNA levels in the myocardia. The maximal binding capacity of [3H]ghrelin for myocardial sarcolemma was higher in ISO-treated rats than in controls. Ghrelin administration improved cardiac function and ameliorated cardiomegaly and attenuated myocardial lipid peroxidation injury and relieved cardiac fibrosis as compared with ISO treatment alone. Administration of des-octanoyl ghrelin effectively antagonized ISO-induced myocardial injury and improved all parameters measured. However, the therapeutic effect of des-octanoyl ghrelin was significantly weaker than that of ghrelin. The plasma growth hormone level increased markedly, by 1.5-fold (P<0.01), with ghrelin administration as compared with that in controls, but was unaltered in des-octanoyl ghrelin group.
CONCLUSION
Myocardial ghrelin and GHSR were up-regulated during ISO-induced myocardial injury. The protective effect of ghrelin against ISO-induced cardiac function injury and fibrosis was more potent than that of des-octanoyl ghrelin, which suggests that ghrelin could be an endogenous cardioprotective factor in ischemic heart disease, and that its effects include growth hormone-dependent and -independent pathways.
目的
确定胃饥饿素和去辛酰基胃饥饿素对异丙肾上腺素诱导的大鼠心肌损伤的心脏保护作用。
方法
大鼠分别于第1、2和3天皮下注射异丙肾上腺素（ISO；20、10和5mg/kg），随后在接下来的7天内每天两次注射3mg/kg，同时给予或不给予胃饥饿素或去辛酰基胃饥饿素（100μg/kg）。采用放射免疫分析法测定血浆胃饥饿素和生长激素水平。用逆转录聚合酶链反应（RT-PCR）检测生长激素促分泌素受体（GHSR）和胃饥饿素mRNA。通过受体结合试验测定[3H]胃饥饿素的最大结合容量和亲和力。
结果
与对照组相比，ISO处理的大鼠表现出严重的心肌损伤、心脏肥大、梗死样坏死和大量纤维化，血浆中免疫反应性胃饥饿素（ir-胃饥饿素）含量增加67%，心肌中增加66%，心肌中mRNA水平增加93%（P<0.01）。ISO处理的大鼠心肌中GHSR mRNA水平高95%（P<0.01）。ISO处理的大鼠心肌肌膜对[3H]胃饥饿素的最大结合容量高于对照组。与单独ISO处理相比，给予胃饥饿素可改善心脏功能，减轻心脏肥大，减轻心肌脂质过氧化损伤，缓解心脏纤维化。给予去辛酰基胃饥饿素可有效拮抗ISO诱导的心肌损伤并改善所有测量参数。然而，去辛酰基胃饥饿素的治疗效果明显弱于胃饥饿素。与对照组相比，给予胃饥饿素后血浆生长激素水平显著升高1.5倍（P<0.01），而去辛酰基胃饥饿素组未改变。
结论
ISO诱导的心肌损伤期间心肌胃饥饿素和GHSR上调。胃饥饿素对ISO诱导的心脏功能损伤和纤维化的保护作用比去辛酰基胃饥饿素更强，这表明胃饥饿素可能是缺血性心脏病中的一种内源性心脏保护因子，其作用包括生长激素依赖性和非依赖性途径。
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