Cardiac and Renal Effects of Growth Hormone in Volume Overload–Induced Heart Failure

Pagel, Ines; Langenickel, Thomas; Höhnel, Klaus; Philipp, Sebastian; Nüssler, Andreas K.; Blum, Werner; Aubert, Michel L.; Dietz, Rainer; Willenbrock, Roland

doi:10.1161/hy0102.098323

Cited by 15 publications

(11 citation statements)

References 29 publications

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“…The inconsistent and contradictory effects of GH or IGF-1 administration on experimental post-MI models have been shown to be dependent on the timing of the treatment, the stage of the disease at treatment initiation, and different dosing regimens (8) and might be related to the heterogeneous origin of treatment (15). In most studies, early treatment with recombinant human GH improves cardiac function and reduces LV remodeling (5,16,17), whereas other studies did not show beneficial effects (15,18). Similarly, treatment with rrGH did not show beneficial effect in rats with large MI (19).…”

Section: Discussionmentioning

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.

100

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%

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.

100

123

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“…Previous reports showed that ghrelin treatment increased serum GH and IGF-1 concentrations (2,5) and that GH and IGF-1 exerted a tissue-protective action through endothelial NO formation (11,12). IGF-1 releases NO via activation of phosphatidyl inositol-3 kinase (PI3K) and its downstream effector Akt (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

“…There have also been reports on the renal protective effects of GH and IGF-1 against various types of renal damage (9), although several other reports did not confirm this effect (10). As for the renal protective mechanism, induction of nitric oxide (NO) and cGMP in the kidney by GH and IGF-1 were suggested to improve renal circulation (11,12).…”

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confidence: 99%

Ghrelin Improves Renal Function in Mice with Ischemic Acute Renal Failure

Takeda¹,

Nishimatsu²,

Suzuki

et al. 2006

Journal of the American Society of Nephrology

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Growth hormone and IGF-1 have been suggested to have tissue-protective effects. Ghrelin is a stomach-derived growth hormone secretagogue. The effects of ghrelin on ischemia/reperfusion-induced renal failure in mice were examined. Ischemic acute renal failure was induced by bilateral renal artery clamping for 45 min and reperfusion for 24 h. Ghrelin (100 g/kg mouse) or vehicle was injected subcutaneously six times before surgery and three times after surgery every 8 h. Twenty-four hours after reperfusion, the right kidney was isolated and perfused. Acetylcholine (ACh)-and adrenomedullin-induced endothelium-dependent vasorelaxation of renal vessels significantly improved in ghrelin-pretreated mice (%⌬ renal perfusion pressure by 10 ؊7 M ACh ؊63.5 ؎ 3.7 versus ؊41.2 ؎ 5.5%; P < 0.05). This change was associated with significant increases of nitric oxide release in the kidneys of ghrelin-treated mice (10 ؊7 M ACh 35.5 ؎ 5.8 versus 16.9 ؎ 3.5 fmol/g kidney per min; P < 0.05). Serum concentration of urea nitrogen (53 ؎ 7 versus 87 ؎ 15 mg/dl; P < 0.05) and renal injury score were significantly lower in the ghrelin group (2.5 ؎ 0.8 versus 5.3 ؎ 1.5; P < 0.01). Tubular apoptotic index was significantly lower in the ghrelin group (5 ؎ 5 versus 28 ؎ 4; P < 0.05). Furthermore, the survival rate after the 60-min ischemic period was higher in the ghrelin group (80 versus 20%; P < 0.05). Ghrelin treatment significantly increased the serum level of IGF-1. However, such renal protective effects of ghrelin on ischemia/reperfusion injury were not observed in insulin receptor substrate-2 knockout mice. These results suggest that ghrelin may protect the kidneys from ischemia/reperfusion injury and that this effect is related to an improvement of endothelial function through an IGF-1-mediated pathway.

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“…The infrarenal Aortocaval Shunt (ACS) in male Wistar rats (weight on average 250 g) was used as a model of volume overload-induced heart failure as previously described [5][6][7]. Sham-operated rats used as controls were treated identically, except that no puncture of the vessels was performed.…”

Section: Methodsmentioning

confidence: 99%

“…We used the model of aortocaval shunt induced cardiac failure [5][6][7]. To identify the different properties of these substances we used the ACS model, in which fibrosis is negligible.…”

Section: Introductionmentioning

confidence: 99%

Induction of Hypoxia Inducible Factor Rather than Modulation of Collagen Metabolism Improves Cardiac Function and Reduces Left Ventricular Hypertrophy after Aortocaval Shunt in Rats

Philipp¹

2012

J Clin Exp Cardiolog

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Introduction: Matrix reorganization and collagen formation have been suggested to be responsible for cardiac remodeling. Recently, Hypoxia Inducible Factors (HIF) has been shown to be also involved. To differentiate the pathogenesis of cardiac remodeling we used two different prolyl 4-hydroxylase (P4H) inhibitors, FG 0041 known for its potential in reducing collagen formation, FG 2216 for its capability to induce HIF. This study was performed to analyze whether the beneficial effects of P4-HI are mediated by induction of HIF or by effects on collagen metabolism.Methods: 8-week-old Wistar rats either had sham operations (n=14) or received Aortocaval Shunt (ACS). From day 2 rats received P4-HI (n=10 for each P4-HI) or vehicle (n=15) by oral gavage. Echocardiography was performed 28 days after ACS; hemodynamic measurements were done after 30 days. Activity of the metalloproteinase 2 and its inhibitor (TIMP), mRNA levels of CTGF, TGFß1, ITGß1 and Collagen I and III protein were measured.Results: After 30 days both HIF was induced in ACS. Treatment with FG 2216 led to an increase of HIF after 30 days compared to FG 0041 and vehicle. Only FG 2216 prevented left ventricular end-diastolic (7.9 mm vs. 9.8 mm; p<0.001) and end-systolic (4.1 vs. 6.0 mm, p<0.001) dilatation and improved left ventricular ejection fraction (85% vs. 74%, p<0.05). Heart weight (1416 ± 71 vs. 1871 ± 51 mg, p<0.001) and lung weight, as a marker for heart failure, (1958 ± 102 mg vs. 2276 ± 105 mg, p<0.05) were lower in the group receiving FG 2216. Collagen protein and metalloproteinase activity accompanying ACS were significantly decreased by FG 0041, but not by FG 2216. Conclusion:Induction of HIF improves cardiac function and reduces cardiac hypertrophy independent of changes in mRNA, collagen protein or metalloproteinase activity in this model of hypertrophy. Thus FG 2216 affects remodeling by directly targeting cardiomyocytes and has negligible effect on collagen production or extracellular matrix composition.

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Cardiac and Renal Effects of Growth Hormone in Volume Overload–Induced Heart Failure

Cited by 15 publications

References 29 publications

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

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

Ghrelin Improves Renal Function in Mice with Ischemic Acute Renal Failure

Induction of Hypoxia Inducible Factor Rather than Modulation of Collagen Metabolism Improves Cardiac Function and Reduces Left Ventricular Hypertrophy after Aortocaval Shunt in Rats

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