Ghrelin在心血管系统中的作用

Ghrelin是生长激素促分泌素受体的内源性配体.在心血管系统中,ghrelin通过特定的受体,介导舒张血管、增强心肌收缩力、保护心血管系统等生物学作用,对ghrelin的研究,有助于认识心力衰竭、心肌梗死、中毒性休克等疾病.     

Ghrelin在心血管系统中的作用

Ghrelin是生长激素促分泌素受体的内源性配体。在心血管系统中,ghrelin通过特定的受体,介导舒张血管、增强心肌收缩力、保护心血管系统等生物学作用,对ghrelin的研究,有助于认识心力衰竭、心肌梗死、中毒性休克等疾病。     

Ghrelin与生长激素关系的研究进展

Ghrelin是最近发现的一种脑-肠肽,具有强烈的促生长激素（GH）释放的作用,此外还能调节能量代谢、食欲、睡眠等.目前认为,ghrelin可同时作用于人体腺垂体和下丘脑,与促生长激素释放激素协同促进GH分泌.Ghrelin的分泌具有性别差异,可被生长抑素抑制,但外周GH水平对ghrelin的分泌无明显影响.另外,胰岛素样生长因子1可通过下调ghrelin受体的表达而影响其作用.     

Ghrelin与生长激素关系的研究进展

Ghrelin是最近发现的一种脑—肠肽,具有强烈的促生长激素(GH)释放的作用,此外还能调节能量代谢、食欲、睡眠等。目前认为,ghrelin可同时作用于人体腺垂体和下丘脑,与促生长激素释放激素协同促进GH分泌。Ghrelin的分泌具有性别差异,可被生长抑素抑制,但外周GH水平对ghrelin的分泌无明显影响。另外,胰岛素样生长因子1可通过下调ghrelin受体的表达而影响其作用。     

Ghrelin和糖尿病

Ghrelin是近年来发现的一种内源性生长激素促分泌剂受体的配体.大量研究已证实,ghrelin不仅能促进生长激素的分泌,而且还具有增加体重及调节能量代谢的作用.新近研究发现,ghrelin与胰岛素及糖脂代谢密切相关,低ghrelin水平可以作为2型糖尿病和糖耐量减低的一个危险因子,并且ghrelin还参与炎症及免疫应答的调节.     

Ghrelin对心血管系统作用的研究进展

本文主要就ghrelin的生物学效应,特别是在心血管方面的作用作一综述。Ghrelin是新发现的一种胃肠多肽,作用于下丘脑和垂体,可刺激生长激素(GH)释放,增强食欲,促进脂肪堆积。Ghrelin依赖于第3位丝氨酸残基辛酰基化的特征性结构,与一种G蛋白偶联受体结合,发挥内分泌调节作用。值得注意的是,ghrelin具有独立于生长激素之外的心脏保护作用。     

Ghrelin对胰腺功能的影响

Ghrelin是生长激素促泌剂受体的内源性配体。作为中枢神经一消化器官轴系统中的多肽,ghrelin及其受体广泛分布于中枢神经系统(下丘脑、垂体)和消化系统(胃、肠、胰腺)中。Ghrelin具有增加胃酸分泌、提高胃肠蠕动、促进生长激素分泌、促进食欲、调节能量代谢等多种作用。研究证明,ghrelin不仅影响胰腺的内分泌功能,而且也影响胰腺的外分泌功能。这为今后胰腺内、外分泌功能的研究提供了新的方向。     

Ghrelin的心血管效应及作用机制

Ghrelin是一种体内生长激素促分泌素受体的内源性配体,其除了能促进生长激素分泌外,在体内许多器官系统还发挥着重要作用。Ghrelin在心血管系统中的作用,包括:改善内皮细胞功能失调、抗心肌细胞凋亡、增加射血分数、扩张外周血管和减轻心脏缺血/再灌注损伤等。现重点阐述ghrelin的心血管效应及其作用机制。     

Ghrelin和糖尿病

Ghrelin是近年来发现的一种内源性生长激素促分泌剂受体的配体。大量研究已证实,ghrelin不仅能促进生长激素的分泌,而且还具有增加体重及调节能量代谢的作用。新近研究发现,ghrelin与胰岛素及糖脂代谢密切相关,低ghrelin水平可以作为2型糖尿病和糖耐量减低的一个危险因子,并且ghrelin还参与炎症及免疫应答的调节。     

Ghrelin的心血管作用及其机制的研究进展

Ghrelin是生长激素促分泌素受体（growth hormone secretagogue receptor,GHSR）的内源性配体,其作用广泛,町刺激垂体释放生长激素（growth hormone,GH）,参与能量代谢以及影响其他激素及细胞因子的释放。近年来研究发现,ghrelin及其合成类似物可以通过分布在心血管系统的相关受体改善心脏收缩、减少冠状动脉粥样硬化相关因子的表达,舒张血管,改善灌注等保护作用,有潜在研发成心血管药物的可能。现对ghrelin对心血管的作用及其作用机制作一综述。     

Growth hormone releasing peptide (ghrelin) is synthesized and secreted by cardiomyocytes

OBJECTIVE: Ghrelin, the endogenous ligand of growth hormone secretagogue receptor (GHS-R), acts on the pituitary and the hypothalamus to stimulate the release of growth hormone (GH) and promotes appetite and adiposity. It has also been reported to increase myocardial contractility, induce vasodilation, and protect against myocardial-infarction-induced heart failure. Though principally gastric in origin, it is also produced by other tissues. This work investigated whether cardiomyocytes synthesize and secrete ghrelin, and how its production in these cells responds to stress and exogenous apoptotic agents. METHODS: Ghrelin and its receptor expression was studied by RT-PCR, immunohistochemistry, and competitive binding studies in mouse adult cardiomyocyte cell line HL-1, and primary cultured human cardiomyocytes. Ghrelin accumulation in cardiomyocyte culture medium was measured by radioimmunoassay. Viability and apoptosis assays were carried on by MTT and Hoechst dye vital staining, respectively. RESULTS: RT-PCR showed that HL-1 cells produce mRNAs for both ghrelin and GHS-R, and that GHS-R1a is expressed in human cardiomyocytes; and competitive binding studies using (125)I-labelled ghrelin showed efficient constitutive expression of GHS-R at the surface of HL-1 cells. Immunohistochemistry confirmed the presence of ghrelin in the cytoplasm of HL-1 cells and of isolated human cardiomyocytes in primary culture. Radioimmunoassay showed that ghrelin was secreted by HL-1 cells and human cardiomyocytes into the culture medium. Ghrelin did not modify the viability of HL-1 cells subjected to 12-h starvation, but did protect against the apoptosis inducer cytosine arabinoside (AraC). Finally, production of ghrelin mRNA in HL-1 cardiomyocytes was reduced by AraC but increased if exposure to AraC was preceded by GH treatment. CONCLUSIONS: Ghrelin is synthesized and secreted by isolated murine and human cardiomyocytes, probably with paracrine/autocrine effects, and may be involved in protecting these cells from apoptosis.     

Ghrelin与慢性心力衰竭

Ghrelin是近年来发现的一种肽类激素,是生长激素促泌物受体(GHS-R)的内源性配体。Ghrelin除了刺激生长激素分泌外,还具有许多其他的生理作用。研究发现:在心血管疾病特别是慢性心力衰竭的治疗方面具有潜在的功效。     

Ghrelin and synthetic growth hormone secretagogues are cardioactive molecules with identities and differences

Ghrelin, a 28-amino acid peptide mainly produced by the stomach, is a natural ligand of the type 1a growth hormone secretagogue receptor (GHS-R1a) that also binds synthetic peptidyl and nonpeptidyl GHSs. GHS-R1a and various GHS-R1a-related receptor subtypes are widely distributed in central and peripheral tissues, particularly in the cardiovascular system. In agreement with this distribution of GHS-R, ghrelin and synthetic GHSs exert a wide spectrum of actions, including cardiac and vascular activities. Ghrelin, as well as peptidyl and nonpeptidyl GHSs, is able to increase cardiac performances both in animals and in humans and to exert protective effects on ischemia/reperfusion injury of isolated rat heart. Moreover, both ghrelin and synthetic GHSs have been shown as able to act as survival factors, protecting cardiomyocytes and endothelial cells from doxorubicin-induced apoptosis. Despite the fact that the neuroendocrine actions of ghrelin are dependent on its acylation in serine 3, these cardiovascular effects are exerted by unacylated as well as by acylated ghrelin. This evidence indicates that these actions are not likely to be mediated by a type 1a GHS-R, which, by definition, binds acylated ghrelin only. However, synthetic peptidyl GHSs, but not nonpeptidyl, and even ghrelin itself are able to reduce atherosclerotic lesion development in apolipoprotein-E-deficient mice. This action seems to be mediated by a specific receptor for synthetic peptidyl GHSs only, identified as CD36, a multifunctional B-type scavenger receptor involved in atherogenesis and mainly expressed in cardiomyocytes and microvascular endothelial cells. Thus, there are similarities, but also differences, between ghrelin and synthetic GHSs, in terms of cardiac actions that are likely to be related to the existence of multiple GHS-R subtypes that mediate the cardiovascular actions of the above substances. These actions indicate their potential pharmacotherapeutic implications in cardiovascular diseases.     

Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man

OBJECTIVE: Ghrelin is the recently identified endogenous ligand for the ghrelin receptor GHS-R1a and known to regulate growth hormone secretion and appetite. Ghrelin also is a potent vasodilator and improves cardiac performance after systemic administration. Generally, the octanoyl modification on Ser3 has been considered essential for biological activity. Recently however, cardiovascular actions of des-octanoyl ghrelin have been reported in rodents. Our aim was to investigate if ghrelin and ghrelin receptor protein are expressed within the human vasculature, to determine if des-octanoyl ghrelin, like ghrelin, is a vasodilator in human artery and to test the acute effect of ghrelin peptides on cardiac contractility. METHODS: Distribution of ghrelin and ghrelin receptor was determined using standard immunocytochemistry and confocal microscopy. Ghrelin peptides were tested for vasodilator actions in human isolated arteries and their effect on cardiac contractility was investigated in human isolated paced atria. RESULTS: Immunoreactive ghrelin was detected in endothelial cells of human arteries and veins where it localized to intracellular vesicles but not to the Weibel-Palade bodies of the regulated pathway, suggesting constitutive ghrelin production. Specific antisera detected ghrelin receptor on vascular smooth muscle cells and cardiomyocytes. Ghrelin (pD2=8.60+/-0.1, Emax=55.8+/-8.9, mean+/-standard error of the mean) and des-octanoyl ghrelin (pD2=8.8+/-0.2, Emax=54.7+/-5.3) showed comparable (P>0.05) endothelium independent vasodilator potency and efficacy in reversing endothelin-1 induced constriction in human artery. Neither ghrelin nor des-octanoyl ghrelin had effects on contractile force in paced atria. CONCLUSIONS: We show widespread expression of ghrelin and its cognate receptor in the human cardiovascular system with functional evidence suggesting a role for both ghrelin and the more abundant endogenous form des-octanoyl ghrelin in the paracrine regulation of vascular tone in man.     

Developments in ghrelin biology and potential clinical relevance.

The spiropiperidine, MK0677, has been exploited to characterize and expression clone the growth hormone secretagogue receptor (GHS-R). Cloning of this receptor led to identification of its natural ligands, ghrelin and adenosine. Targeted disruption of the Ghsr gene demonstrated unambiguously that the GH-releasing and orexigenic properties of ghrelin are dependent on Ghsr expression and that the orexigenic signal is mediated through neuropeptide Y and agouti-related peptide neurons. This review summarizes new developments in our understanding of the physiological roles of ghrelin and its receptor (GHS-R). Recent discoveries of the effects of ghrelin on the thymus and proinflammatory and chemotactic cytokine pathways stimulate renewed interest in potential clinical applications, which include age-associated disorders, such as metabolic disease, sarcopenia, congestive heart failure, atherosclerosis and anorexia.     

The ghrelin axis in disease: potential therapeutic indications

Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produced predominantly in the stomach. It is present in the circulation in two major forms, an acylated and an unacylated form, both of which have reported activities. Some of the best understood actions of acylated ghrelin administration are its orexigenic effects, and the stimulation of GH secretion. Ghrelin also seems to play a role in glucose homeostasis, lipid metabolism and immune function. Based on its orexigenic and metabolic effects, ghrelin and ghrelin mimetics have potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal, cardiac and pulmonary disease, and age-related frailty. Ghrelin also has potentially useful positive effects on cardiac function and gastric motility. Ghrelin antagonists may be of benefit to increase insulin sensitivity and potentiate weight loss. The following chapter presents some background on ghrelin and ghrelin assays and discusses some of the potential therapeutic approaches for the use of ghrelin, ghrelin mimetic compounds and ghrelin antagonists in clinical disease.     

Ghrelin and cardiovascular diseases

In 1999, a peptide from the stomach called ghrelin was discovered, which exerts potent growth hormone releasing powers. Subsequent studies revealed that it exerts a potent orexigenic action. In addition, the beneficial effects of ghrelin in cardiovascular diseases have been recently suggested. In humans as well as in animals, administration of ghrelin improves cardiac function and remodeling in chronic heart failure. In an animal model for myocardial infarction, ghrelin treatment early after coronary ligation effectively reduces fatal arrhythmia and, consequently, mortality, suggesting the potential therapeutic role of the peptide in acute myocardial infarction. Although how ghrelin may influence the cardiovascular system is not fully understood, the cardiovascular beneficial effects are mediated possibly through a combination of various actions, such as an increase in growth hormone level, an improvement in energy balance, direct actions to the cardiovascular cells, and regulation of the autonomic nervous activity. Of note, current experimental evidence suggests that ghrelin may act centrally to decrease sympathetic nervous system activity through peripheral afferent nerve. Thus, administration of ghrelin might become a unique new therapy for cardiovascular diseases.     

One dose of ghrelin prevents the acute and sustained increase in cardiac sympathetic tone after myocardial infarction

Acute myocardial infarction (MI) increases sympathetic nerve activity (SNA) to the heart, which exacerbates chronic cardiac deterioration. The hormone ghrelin, if administered soon after an MI, prevents the increase in cardiac SNA and improves early survival prognosis. Whether these early beneficial effects of ghrelin also impact on cardiac function in chronic heart failure has not yet been addressed and thus was the aim of this study. MI was induced in Sprague Dawley rats by ligating the left coronary artery. One bolus of saline (n = 7) or ghrelin (150 μg/kg, sc, n = 9) was administered within 30 min of MI. Two weeks after the infarct (or sham; n = 7), rats were anesthetized and cardiac function was evaluated using a Millar pressure-volume conductance catheter. Cardiac SNA was measured using whole-nerve electrophysiological techniques. Untreated-MI rats had a high mortality rate (50%), evidence of severe cardiac dysfunction (ejection fraction 28%; P < 0.001), and SNA was significantly elevated (102% increase; P = 0.03). In comparison, rats that received a single dose of ghrelin after the MI tended to have a lower mortality rate (25%; P = NS) and no increase in SNA, and cardiac dysfunction was attenuated (ejection fraction of 43%; P = 0.014). This study implicates ghrelin as a potential clinical treatment for acute MI but also highlights the importance of therapeutic intervention in the early stages after acute MI. Moreover, these results uncover an intricate causal relationship between early and chronic changes in the neural control of cardiac function in heart failure.     

Ghrelin, a novel growth hormone-releasing peptide, in the treatment of cardiopulmonary-associated cachexia

Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, which has been identified as an endogenous ligand for GH secretagogue receptor. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. This peptide also stimulates food intake and induces adiposity through GH-independent mechanisms. In addition, ghrelin acts directly on the central nervous system to decrease sympathetic nerve activity. Thus, ghrelin plays important roles for maintaining GH release and energy homeostasis. Repeated administration of ghrelin improves body composition, muscle wasting, functional capacity, and sympathetic augmentation in cachectic patients with heart failure or chronic obstructive pulmonary disease. These results suggest that ghrelin has anti-cachectic effects through GH-dependent and independent mechanisms. Thus, administration of ghrelin may be a new therapeutic strategy for the treatment of cardiopulmonary-associated cachexia.