Cardioprotective effects of ghrelin and des-octanoyl ghrelin on myocardial injury induced by isoproterenol in rats.
OBJECTIVE
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.


CONCLUSIONS
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.
Li
Lian
L
Institute of Cardiovascular Research, Peking University First Hospital, Beijing 100034, China.
Zhang
Li-Ke
LK
Pang
Yong-Zheng
YZ
Pan
Chun-Shui
CS
Qi
Yong-Fen
YF
Chen
Li
L
Wang
Xian
X
Tang
Chao-Shu
CS
Zhang
Jing
J
D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D005355:Fibrosis; D054439:Ghrelin; D013006:Growth Hormone / Q000097:blood; D007545:Isoproterenol; D008297:Male; D017202:Myocardial Ischemia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D036361:Peptide Hormones / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis* / Q000235:genetics; D054440:Receptors, Ghrelin; D012508:Sarcolemma / Q000378:metabolism
D002316:Cardiotonic Agents; D054439:Ghrelin; D036361:Peptide Hormones; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; C422650:ghrelin, des-n-octanoyl; D013006:Growth Hormone; D007545:Isoproterenol