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

Andrea Benso, Fabio Broglio, Lisa Marafetti, Barbara Lucatello, Maria Angela Seardo, Riccarda Granata, Valentino Martina, Mauro Papotti, Giampiero Muccioli, Ezio Ghigo
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引用次数: 26

Abstract

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.

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胃促生长素和合成生长激素促分泌剂是两种不同的促心脏活性分子。
Ghrelin是一种主要由胃产生的含有28个氨基酸的肽,是1a型生长激素促分泌素受体(GHS-R1a)的天然配体,也能结合合成的肽基和非肽基ghs。GHS-R1a和各种GHS-R1a相关受体亚型广泛分布于中枢和外周组织,特别是心血管系统。与GHS-R的这种分布一致,ghrelin和合成ghs发挥广泛的作用,包括心脏和血管活动。Ghrelin以及肽基和非肽基GHSs均能提高动物和人的心脏性能,并对离体大鼠心脏缺血再灌注损伤具有保护作用。此外,ghrelin和合成GHSs都被证明能够作为存活因子,保护心肌细胞和内皮细胞免受阿霉素诱导的凋亡。尽管饥饿素的神经内分泌作用依赖于其丝氨酸3的酰化,但这些心血管作用可通过未酰化和酰化的饥饿素发挥作用。这一证据表明,这些作用不太可能是由1a型GHS-R介导的,根据定义,1a型GHS-R仅结合酰化的饥饿素。然而,合成肽基GHSs,而非肽基GHSs,甚至胃饥饿素本身都能够减少载脂蛋白e缺乏小鼠的动脉粥样硬化病变发展。这种作用似乎仅由合成肽基GHSs的特异性受体介导,该受体被鉴定为CD36,这是一种参与动脉粥样硬化的多功能b型清道夫受体,主要表达于心肌细胞和微血管内皮细胞。因此,在心脏作用方面,胃饥饿素和合成ghs有相似之处,但也有差异,这可能与多种GHS-R亚型的存在有关,这些亚型介导上述物质的心血管作用。这些作用表明它们在心血管疾病中的潜在药物治疗意义。
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