Aims To test the hypothesis that the activation of the growth hormone-releasing hormone (GHRH) receptor signaling 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 ischemic cardiomyopathy, independently of the growth-hormone axis. Methods and Results 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 growth hormone-releasing hormone, 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. Conclusion These findings indicate that the GHRH receptor signaling 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. Translational Perspective Heart failure with preserved ejection fraction (HFpEF) presents with left-ventricular hypertrophy (LVH), diastolic dysfunction and a spectrum of systemic co-morbidities. Developing animal models and successful therapeutics is notoriously challenging. Here, we used low dose angiotensin-II infusion in mice, which produced LVH, diastolic dysfunction, myocardial fibrosis, and heart failure, and tested growth hormone releasing hormone (GHRH)-agonists, known to have cardiac anti-hypertophic and pro-regenerative effects, on reversing and preventing the angiotensin-II phenotype. We demonstrate improved myocardial relaxation, diastolic calcium handing, and cardiac fibrosis, opening the possibility of using GHRH-agonists for HFpEF. Testing in other animal models and clinical studies are warranted.

中文翻译：

---

合成生长激素释放激素激动剂改善 HFpEF 的心肌病理生理学特征

目的 检验心肌内生长激素释放激素 (GHRH) 受体信号通路的激活既可以预防也可以逆转舒张功能障碍和与射血分数保留性心力衰竭 (HFpEF) 一致的病理生理学特征的假设。心肌松弛受损、纤维化和心室僵硬以及其他多器官疾病是 HFpEF 综合征潜在表型的特征。尽管 HFpEF 的患病率迅速增加，但几乎没有出现有效的治疗方法。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性能，与生长激素轴无关。方法和结果 CD1 小鼠接受血管紧张素-II (Ang-II) 连续输注 4 周或 8 周，以产生具有与 HFpEF 一致的几个特征的表型。小鼠被给予载体或生长激素释放激素的有效合成激动剂 MR-356，持续 4 周，同时开始或在开始 Ang-II 输注后 4 周。Ang-II治疗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。从这些动物中分离出的心肌细胞表现出不完全松弛、收缩反应抑制、肌原纤维蛋白磷酸化改变和钙处理机制紊乱（离体）。MR-356 在体内和体外均能预防和逆转病理表型的发展。GHRH 受体的激活增加了从对照动物分离的心肌细胞中的 cAMP 和 cGMP，但仅增加了心脏成纤维细胞中的 cAMP，这表明 GHRH-A 对心肌细胞和成纤维细胞产生不同的影响。结论 这些发现表明 GHRH 受体信号通路代表了一个新的分子靶点，通过靶向肌丝磷酸化和纤维化来抵消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 受体可能提供一种新的治疗方法来管理与 HFpEF 综合征相关的心肌改变。转化观点 射血分数保留的心力衰竭 (HFpEF) 表现为左心室肥大 (LVH)、舒张功能障碍和一系列全身合并症。开发动物模型和成功的治疗方法是出了名的具有挑战性。在这里，我们在小鼠中使用了低剂量血管紧张素-II 输注，这会产生 LVH、舒张功能障碍、心肌纤维化和心力衰竭，并测试了生长激素释放激素 (GHRH) 激动剂，已知其具有心脏抗肥厚和促再生作用对逆转和预防血管紧张素-II 表型的影响。我们证明改善了心肌松弛、舒张期钙传递和心脏纤维化，开启了使用 GHRH 激动剂治疗 HFpEF 的可能性。需要在其他动物模型和临床研究中进行测试。并测试了已知具有抗心脏肥大和促再生作用的生长激素释放激素 (GHRH) 激动剂在逆转和预防血管紧张素 II 表型方面的作用。我们证明改善了心肌松弛、舒张期钙传递和心脏纤维化，开启了使用 GHRH 激动剂治疗 HFpEF 的可能性。需要在其他动物模型和临床研究中进行测试。并测试了已知具有抗心脏肥大和促再生作用的生长激素释放激素 (GHRH) 激动剂在逆转和预防血管紧张素 II 表型方面的作用。我们证明改善了心肌松弛、舒张期钙传递和心脏纤维化，开启了使用 GHRH 激动剂治疗 HFpEF 的可能性。需要在其他动物模型和临床研究中进行测试。