GH-releasing peptides improve cardiac dysfunction and cachexia and suppress stress-related hormones and cardiomyocyte apoptosis in rats with heart failure

Xu, Xiangbin; Pang, Jinjiang; Cao, Ji-Min; Xu, Ruiyi; Peng, Xiaozhong; Yu, Xianpeng; Guo, Songjun; Chen, Meng-Chin; Chen, Chen

doi:10.1152/ajpheart.01042.2004

Cited by 68 publications

(62 citation statements)

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“…8) Hexarelin, a synthetic analog of ghrelin, shows effects similar to those of ghrelin and is more chemically stable, making it a potential alternative to ghrelin. Its beneficial action on the cardiovascular system has been reported by a lot of research, including inhibition of cardiomyocyte apoptosis, [9][10][11] anti-atherosclerosis, 12,13) improving cardiac output, [14][15][16][17] and suppressing cardiac fibrosis. 18) These effects are considered to be mediated not only by GHSR1a but also by activation of cardiac CD36 receptors.…”

Section: Discussionmentioning

confidence: 99%

The Growth Hormone Secretagogue Hexarelin Protects Rat Cardiomyocytes From <i>in vivo</i> Ischemia/Reperfusion Injury Through Interleukin-1 Signaling Pathway

Huang

Zhang

et al. 2017

Int. Heart J.

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SummaryHexarelin, a synthetic growth hormone-releasing peptide, has been proven to possess cardioprotective actions through its binding to the growth hormone secretagogue receptor (GHSR) 1a and the non-GHSR receptor CD36. However, its effect on myocardial ischemia/reperfusion (I/R) injury has not been fully clarified in vivo. We aimed to determine whether hexarelin treatment could protect cardiomyocytes from I/R injury and to examine the underlying mechanisms. In vivo hearts of male SD rats underwent 30 minutes of ischemia by left coronary artery ligation followed by reperfusion. The rats were then treated subcutaneously twice daily with hexarelin [100 μg/kg·day], ghrelin [400 μg/ kg·day], or saline for 7 days. Echocardiography, malondialdehyde detection, and histochemical staining were performed after treatment. In addition, Western blot was used to examine the expression levels of IL-1β, IL-1Ra, and IL-1RI. Our study showed that hexarelin treatment improved cardiac systolic function, decreased malondialdehyde production, and increased the number of surviving cardiomyocytes. The beneficial effects of hexarelin treatment were slightly superior to those of equimolar ghrelin treatment. We meanwhile confirmed that hexarelin induced down-regulation of IL-1β expression and up-regulation of IL-1Ra expression in I/R myocardium, which could be neutralized by the GHSR antagonist A cute myocardial infarction, which is caused by a sudden embolism of the coronary arteries, is a leading cause of mortality. As the primary clinical therapy for treatment of myocardial infarction, myocardial reperfusion can also aggravate cardiac injury. 1) Its mechanism includes calcium overload, cardiomyocyte apoptosis, and reactive oxygen species (ROS) accumulation.2-5) Finding a strategy to alleviate myocardial I/R injury has become a hot research field in cardiology.In vivo I/R models can cause regional myocardial I/R injury by ligating the left anterior descending coronary artery, which have been widely used to mimic the process of myocardial infarction and subsequent reperfusion.6) Compared to the in vitro global I/R models, in vivo I/R models can not only reveal changes in hemodynamics, and cardiac structure and function after I/R, but also display the impact of molecules in reperfusion flow on I/R myocardium, such as ROS and inflammation cytokines.7) The in vivo I/R models are more consistent with the pathophysiological process of myocardial I/R injury.Ghrelin, a growth hormone-releasing peptide produced in the stomach, is an endogenous ligand of growth hormone secretagogue receptor (GHSR) 1a. Previous studies have demonstrated the cardioprotective effects of exogenous ghrelin administration. 8) Hexarelin, a synthetic analog of ghrelin, shows effects similar to those of ghrelin and is more chemically stable, making it a potential alternative to ghrelin. Its beneficial action on the cardiovascular system has been reported by a lot of research, including inhibition of cardiomyocyte apoptosis, [9][10][11] anti-atherosclerosis, 12,13) impro...

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Section: Discussionmentioning

confidence: 99%

The Growth Hormone Secretagogue Hexarelin Protects Rat Cardiomyocytes From <i>in vivo</i> Ischemia/Reperfusion Injury Through Interleukin-1 Signaling Pathway

Huang

Zhang

et al. 2017

Int. Heart J.

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“…A c c e p t e d M a n u s c r i p t 13 It has been reported that increased levels of endogenous ghrelin during the progression of doxorubicin-induced cardiomyopathy and heart failure might provide a compensatory self-protective mechanism (Xu et al, 2005). The pathways responsible for this protective effect were investigated in vitro on primary cultured cardiomyocytes challenged with doxorubicin in the presence or absence of ghrelin or a TNF-α antagonist (Xu et al, 2005).…”

Section: Page 13 Of 27mentioning

confidence: 99%

“…The pathways responsible for this protective effect were investigated in vitro on primary cultured cardiomyocytes challenged with doxorubicin in the presence or absence of ghrelin or a TNF-α antagonist (Xu et al, 2005). Ghrelin not only reduced apoptosis and markers of oxidative stress, but also increased antioxidative enzyme activity and retained mitochondrial membrane potential and energy metabolism.…”

Section: Page 13 Of 27mentioning

confidence: 99%

“…Moreover, ghrelin increased mitochondrial antiapoptosis-related gene protein expression, reduced cytoplasmic cytochrome C (Cyt C) release and strengthened the activation of NF-kappaB. Since all these effects were abrogated by the TNF-α antagonist, the authors suggested that the antioxidative and antiapoptotic effects of ghrelin are due to its ability to up regulate TNF-α and involve activation of the TNF-α /NF-kappaB pathways (Xu et al, 2005).…”

Section: Page 13 Of 27mentioning

confidence: 99%

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Ghrelin in cardiovascular disease and atherogenesis

Isgaard

Granata

2011

Molecular and Cellular Endocrinology

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Although initially associated with regulation of appetite, the cardiovascular system has also been recognized as a potentially important target for ghrelin. Moreover, a limited number of clinical studies suggest a role for ghrelin in the treatment of congestive heart failure. So far reported cardiovascular effects of growth hormone secretagogues and/or ghrelin include lowering of peripheral resistance, either direct at the vascular level and/or by modulating sympathetic nervous activity. Other observed effects indicate possible improvement of contractility and cardioprotective effects both in vivo and in vitro.Taken together, these results offer an interesting perspective on the future where further studies aiming at evaluating a role of GHS and ghrelin in the treatment of cardiovascular disease are warranted.

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“…The dosage and duration of Hex treatment (100μg/kg) was applied according to a previous study [266]. Therefore, administration of Hex commenced at week 4 after STZ induction for a subsequent two weeks.…”

Section: Chapter Three -Effect Of Hex On Metbolism Of Animals With/wimentioning

confidence: 99%

The effect of hexarelin in streptozotocin (STZ)-induced rat model through protective actions on islet beta cells and cardiomyocytes

Zhang¹

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Diabetes mellitus (DM) is a major chronic disease, affecting over 300 million people worldwide.Pancreatic islet β-cell dysfunction is known as the major cause of glucose metabolism disorder, which leads to hyperglycemia and eventually DM. Inside the cell, mitochondria perform a crucial role in coupling glucose metabolism to insulin secretion by the β-cell and on other cell functions requiring normal energy balance. Abnormal activity of mitochondria, such as increased apoptosis, contributes to β-cell dysfunction and diabetes related pathological changes in other cell types, for example, depressed growth hormone (GH) secretion was observed in the diabetic state. Cardiac complications of diabetes, also named diabetic cardiomyopathy, account for over 70% of the mortality among diabetic patients, which is characterized as cardiac systolic and diastolic dysfunctions. There are currently no effective targeted treatments. GH secretagogues (GHS) stimulate insulin secretion and GH release in the diabetic rodent model, and protect cardiomyocytes from ischemia/reperfusion injury. To further clarify the mechanism of GHS on diabetes and its cardiovascular complications, the present study employed mouse a β-cell line (MIN6) and streptozotocin (STZ)-induced diabetic rat model treated with the synthetic GHS, hexarelin (Hex), to investigate β-cell function, pulsatile GH secretion and cardiomyocyte contractility.Diabetes was induced by a single dosage of STZ (65mg/kg) IP injection in male Wistar rats with vehicle control group. After 4 weeks of disease development, animals received Hex (100μg/kg) treatment for 2 weeks. In vitro cell study mimicked the in vivo treatment regime; MIN6 cells were exposed to STZ (1mM) for 4 hours followed by a 2 hour Hex (1μM) incubation. Cell viability and mitochondrial function were measured by MTS and Rhodamine assay. Immunohistochemistry of rat pancreas sections was performed to determine islet morphology and apoptosis signaling pathways.ELISA was conducted to examine pulsatile GH and circulating levels of insulin, insulin-like growth factor-1 (IGF-1) and free fatty acids (FFA). Rat cardiomyocyte contractility and intracellular Ca 2+ concentration were investigated by cell shortening and Ca 2+ transient measurement after cardiomyocyte isolation. Whole-cell patch clamp was performed to study membrane potential and transient outward potassium current (I to ). The expression of the GHS receptor, GHS-R, was determined by Western blot. Apoptotic markers were also assessed by protein expression determination in both MIN6 cells and rat cardiomyocytes.II STZ-treated MIN6 cells showed a decrease in cell proliferation and impaired mitochondrial function with increased expression of apoptotic markers, such as caspase-3, caspase-9 and the ratio of Bax/Bcl-2, while incubation of Hex recovered these parameters towards control levels.STZ-induced diabetic rats showed evidence of symptoms of clinical diabetes such as hyperglycemia, polyphagia, polydipsia and polyuria. Body weight gain was decreased in STZ-t...

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GH-releasing peptides improve cardiac dysfunction and cachexia and suppress stress-related hormones and cardiomyocyte apoptosis in rats with heart failure

Cited by 68 publications

References 53 publications

The Growth Hormone Secretagogue Hexarelin Protects Rat Cardiomyocytes From <i>in vivo</i> Ischemia/Reperfusion Injury Through Interleukin-1 Signaling Pathway

The Growth Hormone Secretagogue Hexarelin Protects Rat Cardiomyocytes From <i>in vivo</i> Ischemia/Reperfusion Injury Through Interleukin-1 Signaling Pathway

Ghrelin in cardiovascular disease and atherogenesis

The effect of hexarelin in streptozotocin (STZ)-induced rat model through protective actions on islet beta cells and cardiomyocytes

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