Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure.
Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure.
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DOI：
10.1073/pnas.1712612114
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发表时间：
2017-11-07
影响因子：
11.1
通讯作者：
Granata R
中科院分区：
文献类型：
--
作者：
Gesmundo I;Miragoli M;Carullo P;Trovato L;Larcher V;Di Pasquale E;Brancaccio M;Mazzola M;Villanova T;Sorge M;Taliano M;Gallo MP;Alloatti G;Penna C;Hare JM;Ghigo E;Schally AV;Condorelli G;Granata R
病理性心脏肥大是心力衰竭（HF）的主要危险因素，其特征是心脏响应压力或容量超负荷而生长，例如在高血压背景下。因此，确定预防或逆转心脏肥大的治疗策略是治疗HF的优先事项。已知生长激素释放激素（GHRH）显示心脏保护功能，然而，其在肥大和HF中的治疗潜力尚不清楚。在这里，我们表明GHRH通过抑制肥大途径减少体外心肌细胞肥大。在体内，GHRH类似物MR-409减轻了经受横向主动脉收缩的小鼠的心脏肥大并改善了心脏功能。这些发现表明GHRH类似物用于治疗病理性心脏肥大和HF的治疗用途。研究表明，生长激素释放激素（GHRH）可减少心肌细胞（CM）凋亡，防止缺血/再灌注损伤，改善缺血大鼠心脏功能。然而，目前尚不清楚GHRH是否对危及生命的病理状况有益，如心脏肥大和心力衰竭（HF）。因此，我们在体外和体内测试了GHRH刺激的心肌治疗潜力，使用GHRH或其激动剂类似物MR-409。我们发现，在体外，GHRH（1-44）NH 2减弱苯肾上腺素诱导的肥大H9 c2心肌细胞，成年大鼠心室肌细胞，和人类诱导多能干细胞衍生的CM，减少肥大基因的表达和调节肥大途径。潜在机制包括阻断Gq信号及其下游组分磷脂酶Cβ、蛋白激酶Cε、钙调神经磷酸酶和受磷蛋白。GHRH的受体依赖性作用还包括激活Gαs和cAMP/PKA，抑制cAMP 1直接激活的交换蛋白（Epac 1）的增加。在体内，MR-409减轻了经受横向主动脉缩窄的小鼠的心脏肥大并改善了心脏功能。此外，从用MR-409处理的横向主动脉缩窄小鼠中分离的CM显示出改善的收缩性和肌膜结构的逆转。总体而言，这些结果确定GHRH作为抗肥大调节剂，其潜在的HF治疗潜力，并建议可能有益的使用其类似物治疗病理性心脏肥大。
Pathological cardiac hypertrophy, characterized by heart growth in response to pressure or volume overload, such as in the setting of hypertension, is the main risk factor for heart failure (HF). The identification of therapeutic strategies to prevent or reverse cardiac hypertrophy is therefore a priority for curing HF. It is known that growth hormone-releasing hormone (GHRH) displays cardioprotective functions; however, its therapeutic potential in hypertrophy and HF is unknown. Here we show that GHRH reduces cardiomyocyte hypertrophy in vitro through inhibition of hypertrophic pathways. In vivo, the GHRH analog MR-409 attenuates cardiac hypertrophy in mice subjected to transverse aortic constriction and improves cardiac function. These findings suggest therapeutic use of GHRH analogs for treatment of pathological cardiac hypertrophy and HF. It has been shown that growth hormone-releasing hormone (GHRH) reduces cardiomyocyte (CM) apoptosis, prevents ischemia/reperfusion injury, and improves cardiac function in ischemic rat hearts. However, it is still not known whether GHRH would be beneficial for life-threatening pathological conditions, like cardiac hypertrophy and heart failure (HF). Thus, we tested the myocardial therapeutic potential of GHRH stimulation in vitro and in vivo, using GHRH or its agonistic analog MR-409. We show that in vitro, GHRH(1-44)NH2 attenuates phenylephrine-induced hypertrophy in H9c2 cardiac cells, adult rat ventricular myocytes, and human induced pluripotent stem cell-derived CMs, decreasing expression of hypertrophic genes and regulating hypertrophic pathways. Underlying mechanisms included blockade of Gq signaling and its downstream components phospholipase Cβ, protein kinase Cε, calcineurin, and phospholamban. The receptor-dependent effects of GHRH also involved activation of Gαs and cAMP/PKA, and inhibition of increase in exchange protein directly activated by cAMP1 (Epac1). In vivo, MR-409 mitigated cardiac hypertrophy in mice subjected to transverse aortic constriction and improved cardiac function. Moreover, CMs isolated from transverse aortic constriction mice treated with MR-409 showed improved contractility and reversal of sarcolemmal structure. Overall, these results identify GHRH as an antihypertrophic regulator, underlying its therapeutic potential for HF, and suggest possible beneficial use of its analogs for treatment of pathological cardiac hypertrophy.
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DOI：
10.1038/nrm3495
发表时间：
2013-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
10.8
作者：
Granata, Riccarda;Trovato, Letizia;Ghigo, Ezio
通讯作者：
Ghigo, Ezio
影响因子：
5
作者：
Markou, T;Hadzopoulou-Cladaras, M;Lazou, A
通讯作者：
Lazou, A
影响因子：
20.1
作者：
Metrich, Melanie;Lucas, Alexandre;Lezoualc'h, Frank
通讯作者：
Lezoualc'h, Frank
影响因子：
4.8
作者：
Christensen, AE;Selheim, F;Doskeland, SO
通讯作者：
Doskeland, SO