Cardiac and peripheral actions of growth hormone and its releasing peptides: Relevance for the treatment of cardiomyopathies

Marleau, Sylvie; Mulumba, Mukandila; Lamontagne, Daniel; Ong, Huy

doi:10.1016/j.cardiores.2005.08.022

Cited by 31 publications

(32 citation statements)

References 94 publications

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“…Importantly, all treatments with recombinant human GH in rats had a clear limitation, due perhaps to the production of anti-GH antibodies after 2 weeks of treatment (23). Therefore, the long-term effects (either beneficial or deleterious) remain unknown in these models (8).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to GH itself and IGF-1, GH-releasing peptides such as ghrelin and synthetic GH secretagogues (GHS) are also suggested to have cardiac effects (5)(6)(7)(8), and growth hormone-releasing hormone (GHRH) mRNA is detected in peripheral tissues, including the heart (9, 10), consistent with widespread biologic signaling potential beyond the hypothalamic-pituitary axis.…”

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confidence: 99%

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Cardioprotective effects of growth hormone-releasing hormone agonist after myocardial infarction

Kanashiro‐Takeuchi

Τζιόμαλος

Takeuchi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

123

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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 µg/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.cardiac stem cells | apoptosis | remodeling | heart failure C ongestive heart failure remains a leading cause of morbidity and mortality in developed countries. Despite major therapeutic advances, current therapies fail to fully reverse heart failure and/or left ventricular (LV) dysfunction. One major therapeutic avenue is that of cytokine and/or hormonal signaling pathways, and in this regard, various experimental and clinical studies have suggested an important role for the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the regulation of cardiac growth and function (1, 2). Moreover, several clinical studies have tested the impact of GH replacement on the failing human heart, with controversial results (3, 4).In addition to GH itself and IGF-1, GH-releasing peptides such as ghrelin and synthetic GH secretagogues (GHS) are also suggested to have cardiac effects (5-8), and growth hormone-releasing hormone (GHRH) mRNA is detected in peripheral tissues, including the heart (9, 10), consistent with widespread biologic signaling potential beyond the hypothalamic-pituitary axis.Recently, Granata et al. (10) reported that rat GHRH (1-44) promoted survival of cardiomyocytes in vitro and protected rat hearts from ischemia-reperfusion injury. The detection of the GHRH receptor (GHRHR) on the cardiomyocyte sarcolemmal membrane supports the view that GHRH may elicit direct signal transduction within the heart, independent of the GH/IGF-1 axis per se (10). Ghrelin and other GHS may have pharmacologic potential (10) but also have pleiotropic actions with a high possibility...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cardioprotective effects of growth hormone-releasing hormone agonist after myocardial infarction

Kanashiro‐Takeuchi

Τζιόμαλος

Takeuchi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

123

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“…Studies of rhIGF-I use in heart failure in humans have shown no beneficial effect 60. Studies are ongoing of cardiovascular risk factors comparing the effects of rhGH and rhIGF-I.…”

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confidence: 98%

Mecasermin (recombinant human insulin-like growth factor I)

Rosenbloom

2009

Adv Therapy

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Growth hormone (GH) exercises its growth effects by stimulating insulin-like growth factor I (IGF-I) synthesis in the liver (endocrine IGF-I) and by inducing chondrocyte differentiation/replication and local production of IGF-I (paracrine/autocrine IGF-I). Injectable recombinant human (rh)IGF-I (mecasermin) has been available for nearly 20 years for treatment of the rare instances of GH insensitivity caused by GH receptor defects or GH-inhibiting antibodies. Full restoration of normal growth, as occurs with rhGH replacement of GH deficiency, is not seen, presumably because only the endocrine deficiency is addressed. RhIGF-I has also been effective as an insulin-sensitizing agent in severe insulin-resistant conditions. Although the insulin-sensitizing effect may benefit both type 1 and type 2 diabetes, there are no ongoing clinical trials because of concern about risk of retinopathy and other complications. Promotion of rhIGF-I for treatment of idiopathic short stature has been intensive, with neither data nor rationale suggesting that there might be a better response than has been documented with rhGH. Other applications that have either been considered or are undergoing clinical trial are based on the ubiquitous tissue-building properties of IGF-I and include chronic liver disease, cystic fibrosis, wound healing, AIDS muscle wasting, burns, osteoporosis, Crohn's disease, anorexia nervosa, Werner syndrome, X-linked severe combined immunodeficiency, Alzheimer's disease, muscular dystrophy, amyotrophic lateral sclerosis, hearing loss prevention, spinal cord injury, cardiovascular protection, and prevention of retinopathy of prematurity. The most frequent side effect is hypoglycemia, which is readily controlled by administration with meals. Other common adverse effects involve hyperplasia of lymphoid tissue, which may require tonsillectomy/adenoidectomy, accumulation of body fat, and coarsening of facies. The anti-apoptotic properties of IGF-I are implicated in cancer pathogenesis-a concern for long-term therapy. It is unlikely that mecasermin will be useful beyond the orphan indications of severe insulin resistance and GH insensitivity.

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“…9,13,14 Human growth hormone has also been shown to improve cardiac function in patients with chronic heart failure. 15 We have been interested in TGFb 1 since this growth factor is abundant in platelets, which can limit ischemic injury to the heart. 9 In previous studies, TGFb 1 was shown to reduce apoptosis and necrosis in cultured rat cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of TGFβ1 by adeno-associated virus type-2 vector protects myocardium from ischemia–reperfusion injury

Dandapat

et al. 2007

Gene Ther

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Transforming growth factor b 1 (TGFb 1 ) has been purported to protect tissues from ischemia-reperfusion (I-R) injury. This study was designed to examine if overexpression of TGFb 1 using adeno-associated virus type 2 (AAV) protects cardiomyocytes from reoxygenation injury. TGFb 1 was overexpressed in cultured HL-1 mouse cardiomyocytes by transfection with AAV/TGFb 1 Latent or with AAV/TGFb 1 ACT (active TGFb 1 ). TGFb 1 upregulation reduced cardiomyocyte apoptosis and necrosis induced by 24 h of hypoxia followed by 3 h of reoxygenation concomitant with reduction in reactive oxygen species release, activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and NFkB expression. Transfection with AAV/TGFb 1 ACT was superior to that with AAV/TGFb 1 Latent . To determine if AAV/TGFb 1 ACT upregulation in vivo would induce cardioprotection from I-R injury, rat hearts were injected with AAV/TGFb 1 ACT or phosphate-buffered saline (PBS). Six weeks later, TGFb 1 ACT was upregulated throughout the myocardium. Following I-R, AAV/TGFb 1 ACT -overexpressing rats had much smaller infarct size (Po0.01 vs PBS group), which was also related to reduced activation of NADPH oxidase and NF-kB, and lower levels of malondialdehyde in I-R tissues. These data demonstrate that overexpression of TGFb 1 by AAV can protect cardiac tissues from reperfusion injury, possibly via antioxidant mechanism. These findings suggest potential of TGFb 1 ACT gene therapy for cardioprotection from I-R injury.

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Cardiac and peripheral actions of growth hormone and its releasing peptides: Relevance for the treatment of cardiomyopathies

Cited by 31 publications

References 94 publications

Cardioprotective effects of growth hormone-releasing hormone agonist after myocardial infarction

Cardioprotective effects of growth hormone-releasing hormone agonist after myocardial infarction

Mecasermin (recombinant human insulin-like growth factor I)

Overexpression of TGFβ1 by adeno-associated virus type-2 vector protects myocardium from ischemia–reperfusion injury

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