Growth hormone-releasing hormone promotes survival of cardiac myocytes in vitro and protects against ischaemia-reperfusion injury in rat heart
Growth hormone-releasing hormone promotes survival of cardiac myocytes in vitro and protects against ischaemia-reperfusion injury in rat heart
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DOI：
10.1093/cvr/cvp090
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发表时间：
2009-07-15
影响因子：
10.8
通讯作者：
Ghigo, Ezio
中科院分区：
文献类型：
--
作者：
Granata, Riccarda;Trovato, Letizia;Ghigo, Ezio
下丘脑神经肽生长激素释放激素(GHRH)刺激脑下垂体生长激素的合成和释放。GHRH也对垂体外细胞产生增殖作用，而GHRH拮抗剂已被证明能抑制癌细胞的增殖。逆转录聚合酶链式反应显示成年大鼠心室肌细胞和大鼠心脏H9c2细胞均有GHRH受体(GHRH-R)的mRNA表达。在ARVM中，GHRH可阻止血清饥饿和β-肾上腺素能受体激动剂异丙肾上腺素诱导的细胞死亡和caspase-3激活。GHRH-R拮抗剂JV-1-36在两种实验条件下均可阻断GHRH的存活作用。GHRH诱导的心肌细胞保护需要细胞外信号调节激酶(ERK)1/2和磷脂酰肌醇-3激酶(PI3K)/Akt的激活以及腺苷环化酶/cAMP/蛋白激酶A信号转导。异丙肾上腺素强烈上调促凋亡诱导的cAMP早期抑制因子的mRNA和蛋白，而GHRH则完全阻断这一作用。与抗逆转录病毒药物类似，在H9c2心肌细胞中，GHRH通过相同的信号通路抑制血清饥饿和异丙肾上腺素诱导的细胞死亡和凋亡。最后，GHRH改善了再灌流期间的左心室恢复，并减少了大鼠心肌缺血再灌注(I/R)损伤后的心肌梗死范围。这些作用涉及PI3K/Akt信号通路，并被JV-1-36抑制。我们的研究结果表明，GHRH通过多种信号机制促进心肌细胞存活，并对I/R损伤具有保护作用，表明GHRH具有新的心脏保护作用。
The hypothalamic neuropeptide growth hormone-releasing hormone (GHRH) stimulates GH synthesis and release in the pituitary. GHRH also exerts proliferative effects in extrapituitary cells, whereas GHRH antagonists have been shown to suppress cancer cell proliferation. We investigated GHRH effects on cardiac myocyte cell survival and the underlying signalling mechanisms.Reverse transcriptase-polymerase chain reaction analysis showed GHRH receptor (GHRH-R) mRNA in adult rat ventricular myocytes (ARVMs) and in rat heart H9c2 cells. In ARVMs, GHRH prevented cell death and caspase-3 activation induced by serum starvation and by the beta-adrenergic receptor agonist isoproterenol. The GHRH-R antagonist JV-1-36 abolished GHRH survival action under both experimental conditions. GHRH-induced cardiac cell protection required extracellular signal-regulated kinase (ERK)1/2 and phosphoinositide-3 kinase (PI3K)/Akt activation and adenylyl cyclase/cAMP/protein kinase A signalling. Isoproterenol strongly upregulated the mRNA and protein of the pro-apoptotic inducible cAMP early repressor, whereas GHRH completely blocked this effect. Similar to ARVMs, in H9c2 cardiac cells, GHRH inhibited serum starvation- and isoproterenol-induced cell death and apoptosis through the same signalling pathways. Finally, GHRH improved left ventricular recovery during reperfusion and reduced infarct size in Langendorff-perfused rat hearts, subjected to ischaemia-reperfusion (I/R) injury. These effects involved PI3K/Akt signalling and were inhibited by JV-1-36.Our findings suggest that GHRH promotes cardiac myocyte survival through multiple signalling mechanisms and protects against I/R injury in isolated rat heart, indicating a novel cardioprotective role of this hormone.