Cardioprotective effects of growth hormone-releasing hormone agonist after myocardial infarction.
Whether the growth hormone (GH)/insulin-like growth factor 1(IGF-1) axis exerts cardioprotective effects remains controversial; and the underlying mechanism(s) for such actions are unclear. Here we tested the hypothesis that growth hormone-releasing hormone (GHRH) directly activates cellular reparative mechanisms within the injured heart, in a GH/IGF-1 independent fashion. After experimental myocardial infarction (MI), rats were randomly assigned to receive, during a 4-week period, either placebo (n = 14), rat recombinant GH (n = 8) or JI-38 (n = 8; 50 microg/kg per day), a potent GHRH agonist. JI-38 did not elevate serum levels of GH or IGF-1, but it markedly attenuated the degree of cardiac functional decline and remodeling after injury. In contrast, GH administration markedly elevated body weight, heart weight, and circulating GH and IGF-1, but it did not offset the decline in cardiac structure and function. Whereas both JI-38 and GH augmented levels of cardiac precursor cell proliferation, only JI-38 increased antiapoptotic gene expression. The receptor for GHRH was detectable on myocytes, supporting direct activation of cardiac signal transduction. Collectively, these findings demonstrate that within the heart, GHRH agonists can activate cardiac repair after MI, suggesting the existence of a potential signaling pathway based on GHRH in the heart. The phenotypic profile of the response to a potent GHRH agonist has therapeutic implications.
Division of Cardiology, Department of Medicine, Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Rosemeire M
RM
Kanashiro-Takeuchi
Konstantinos
K
Tziomalos
Lauro M
LM
Takeuchi
Adriana V
AV
Treuer
Guillaume
G
Lamirault
Raul
R
Dulce
Michael
M
Hurtado
Yun
Y
Song
Norman L
NL
Block
Ferenc
F
Rick
Anna
A
Klukovits
Qinghua
Q
Hu
Jozsef L
JL
Varga
Andrew V
AV
Schally
Joshua M
JM
Hare
D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004452:Echocardiography; D005260:Female; D013006:Growth Hormone / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D013007:Growth Hormone-Releasing Hormone / Q000819:agonists* / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D018013:Receptors, Neuropeptide / Q000378:metabolism; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology
D002316:Cardiotonic Agents; C420262:JI-38; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; C048250:somatotropin releasing hormone receptor