Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 N.W. 10th Avenue, Room 908, Miami, FL 33136, USA.
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Cardiovasc Res. 2023 Feb 3;118(18):3586-3601. doi: 10.1093/cvr/cvac098.
To test the hypothesis that the activation of the growth hormone-releasing hormone (GHRH) receptor signalling pathway within the myocardium both prevents and reverses diastolic dysfunction and pathophysiologic features consistent with heart failure with preserved ejection fraction (HFpEF). Impaired myocardial relaxation, fibrosis, and ventricular stiffness, among other multi-organ morbidities, characterize the phenotype underlying the HFpEF syndrome. Despite the rapidly increasing prevalence of HFpEF, few effective therapies have emerged. Synthetic agonists of the GHRH receptors reduce myocardial fibrosis, cardiomyocyte hypertrophy, and improve performance in animal models of ischaemic cardiomyopathy, independently of the growth hormone axis.
CD1 mice received 4- or 8-week continuous infusion of angiotensin-II (Ang-II) to generate a phenotype with several features consistent with HFpEF. Mice were administered either vehicle or a potent synthetic agonist of GHRH, MR-356 for 4-weeks beginning concurrently or 4-weeks following the initiation of Ang-II infusion. Ang-II-treated animals exhibited diastolic dysfunction, ventricular hypertrophy, interstitial fibrosis, and normal ejection fraction. Cardiomyocytes isolated from these animals exhibited incomplete relaxation, depressed contractile responses, altered myofibrillar protein phosphorylation, and disturbed calcium handling mechanisms (ex vivo). MR-356 both prevented and reversed the development of the pathological phenotype in vivo and ex vivo. Activation of the GHRH receptors increased cAMP and cGMP in cardiomyocytes isolated from control animals but only cAMP in cardiac fibroblasts, suggesting that GHRH-A exert differential effects on cardiomyocytes and fibroblasts.
These findings indicate that the GHRH receptor signalling pathway(s) represents a new molecular target to counteract dysfunctional cardiomyocyte relaxation by targeting myofilament phosphorylation and fibrosis. Accordingly, activation of GHRH receptors with potent, synthetic GHRH agonists may provide a novel therapeutic approach to management of the myocardial alterations associated with the HFpEF syndrome.
验证在心肌中激活生长激素释放激素（GHRH）受体信号通路可预防和逆转舒张功能障碍以及射血分数保留心力衰竭（HFpEF）的病理生理特征这一假说。舒张功能障碍、纤维化和心室僵硬度等多种器官病变是 HFpEF 综合征潜在表型的特征。尽管 HFpEF 的患病率迅速上升，但仍缺乏有效的治疗方法。GHRH 受体的合成激动剂可减少心肌纤维化、心肌细胞肥大，并改善缺血性心肌病动物模型的功能，而与生长激素轴无关。
CD1 小鼠接受 4 或 8 周的血管紧张素-II（Ang-II）连续输注以产生具有多种 HFpEF 特征的表型。同时或 Ang-II 输注开始后 4 周开始给予载体或 GHRH 的一种有效的合成激动剂 MR-356 4 周。Ang-II 处理的动物表现出舒张功能障碍、心室肥大、间质纤维化和正常射血分数。从这些动物分离的心肌细胞表现出不完全松弛、收缩反应降低、肌球蛋白重链蛋白磷酸化改变和钙处理机制紊乱（在体）。MR-356 在体内和体外均预防和逆转了病理表型的发展。GHRH 受体的激活增加了来自对照动物的心肌细胞中的 cAMP 和 cGMP，但仅增加了心脏成纤维细胞中的 cAMP，表明 GHRH-A 对心肌细胞和成纤维细胞有不同的作用。
这些发现表明，GHRH 受体信号通路代表了一种新的分子靶点，通过靶向肌丝磷酸化和纤维化来对抗功能失调的心肌细胞松弛。因此，用有效的合成 GHRH 激动剂激活 GHRH 受体可能为管理与 HFpEF 综合征相关的心肌改变提供一种新的治疗方法。
