Activation of growth hormone releasing hormone (GHRH) receptor stimulates cardiac reverse remodeling after myocardial infarction (MI).
Both cardiac myocytes and cardiac stem cells (CSCs) express the receptor of growth hormone releasing hormone (GHRH), activation of which improves injury responses after myocardial infarction (MI). Here we show that a GHRH-agonist (GHRH-A; JI-38) reverses ventricular remodeling and enhances functional recovery in the setting of chronic MI. This response is mediated entirely by activation of GHRH receptor (GHRHR), as demonstrated by the use of a highly selective GHRH antagonist (MIA-602). One month after MI, animals were randomly assigned to receive: placebo, GHRH-A (JI-38), rat recombinant GH, MIA-602, or a combination of GHRH-A and MIA-602, for a 4-wk period. We assessed cardiac performance and hemodynamics by using echocardiography and micromanometry derived pressure-volume loops. Morphometric measurements were carried out to determine MI size and capillary density, and the expression of GHRHR was assessed by immunofluorescence and quantitative RT-PCR. GHRH-A markedly improved cardiac function as shown by echocardiographic and hemodynamic parameters. MI size was substantially reduced, whereas myocyte and nonmyocyte mitosis was markedly increased by GHRH-A. These effects occurred without increases in circulating levels of growth hormone and insulin-like growth factor I and were, at least partially, nullified by GHRH antagonism, confirming a receptor-mediated mechanism. GHRH-A stimulated CSCs proliferation ex vivo, in a manner offset by MIA-602. Collectively, our findings reveal the importance of the GHRH signaling pathway within the heart. Therapy with GHRH-A although initiated 1 mo after MI substantially improved cardiac performance and reduced infarct size, suggesting a regenerative process. Therefore, activation of GHRHR provides a unique therapeutic approach to reverse remodeling after MI.
Interdisciplinary Stem Cell Institute and Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Rosemeire M
RM
Kanashiro-Takeuchi
Lauro M
LM
Takeuchi
Ferenc G
FG
Rick
Raul
R
Dulce
Adriana V
AV
Treuer
Victoria
V
Florea
Claudia O
CO
Rodrigues
Ellena C
EC
Paulino
Konstantinos E
KE
Hatzistergos
Sarah M
SM
Selem
Daniel R
DR
Gonzalez
Norman L
NL
Block
Andrew V
AV
Schally
Joshua M
JM
Hare
D000704:Analysis of Variance; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D013006:Growth Hormone / Q000008:administration & dosage; D013007:Growth Hormone-Releasing Hormone / Q000008:administration & dosage / Q000819:agonists / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006652:Histological Techniques; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008365:Manometry; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D018013:Receptors, Neuropeptide / Q000378:metabolism*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000378:metabolism*; D017337:Sermorelin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D020257:Ventricular Remodeling / Q000187:drug effects*
C550121:GHRH(1-29)NH2, (PhAc-Ada)(0)-Tyr(1), Arg(2), Fpa(5,6), Ala(8), Har(9), Tyr(Me)(10), His(11), Orn(12,) Abu(15), His(20), Orn(21), Nle(27), Arg(28), Har(29)-; C420262:JI-38; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D017337:Sermorelin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; C048250:somatotropin releasing hormone receptor