Berlanga-Acosta Jorge, Cibrian Danay, Valiente-Mustelier Juan, Suárez-Alba José, García-Ojalvo Ariana, Falcón-Cama Viviana, Jiang Baohong, Wang Linlin, Guillén-Nieto Gerardo
Center for Genetic Engineering and Biotechnology, Playa, Cuba.
Institute of Cardiology and Cardiovascular Surgery, Havana, Cuba.
Front Pharmacol. 2024 May 30;15:1402138. doi: 10.3389/fphar.2024.1402138. eCollection 2024.
Dilated cardiomyopathy (DCM) is a fatal myocardial condition with ventricular structural changes and functional deficits, leading to systolic dysfunction and heart failure (HF). DCM is a frequent complication in oncologic patients receiving Doxorubicin (Dox). Dox is a highly cardiotoxic drug, whereas its damaging spectrum affects most of the organs by multiple pathogenic cascades. Experimentally reproduced DCM/HF through Dox administrations has shed light on the pathogenic drivers of cardiotoxicity. Growth hormone (GH) releasing peptide 6 (GHRP-6) is a GH secretagogue with expanding and promising cardioprotective pharmacological properties. Here we examined whether GHRP-6 administration concomitant to Dox prevented the onset of DCM/HF and multiple organs damages in otherwise healthy rats. Myocardial changes were sequentially evaluated by transthoracic echocardiography. Autopsy was conducted at the end of the administration period when ventricular dilation was established. Semiquantitative histopathologic study included heart and other internal organs samples. Myocardial tissue fragments were also addressed for electron microscopy study, and characterization of the transcriptional expression ratio between Bcl-2 and Bax. Serum samples were destined for REDOX system balance assessment. GHRP-6 administration in parallel to Dox prevented myocardial fibers consumption and ventricular dilation, accounting for an effective preservation of the LV systolic function. GHRP-6 also attenuated extracardiac toxicity preserving epithelial organs integrity, inhibiting interstitial fibrosis, and ultimately reducing morbidity and mortality. Mechanistically, GHRP-6 proved to sustain cellular antioxidant defense, upregulate prosurvival gene Bcl-2, and preserve cardiomyocyte mitochondrial integrity. These evidences contribute to pave potential avenues for the clinical use of GHRP-6 in Dox-treated subjects.
扩张型心肌病（DCM）是一种致命的心肌疾病，伴有心室结构改变和功能缺陷，导致收缩功能障碍和心力衰竭（HF）。DCM是接受阿霉素（Dox）治疗的肿瘤患者常见的并发症。Dox是一种具有高度心脏毒性的药物，其损伤范围通过多种致病级联反应影响大多数器官。通过给予Dox实验性复制的DCM/HF揭示了心脏毒性的致病驱动因素。生长激素（GH）释放肽6（GHRP-6）是一种生长激素促分泌素，具有不断扩展且前景广阔的心脏保护药理特性。在此，我们研究了在健康大鼠中，与Dox同时给予GHRP-6是否能预防DCM/HF的发生以及多器官损伤。通过经胸超声心动图对心肌变化进行连续评估。在给药期结束且心室扩张确立时进行尸检。半定量组织病理学研究包括心脏和其他内部器官样本。心肌组织碎片也用于电子显微镜研究以及Bcl-2和Bax转录表达比率的表征。血清样本用于氧化还原系统平衡评估。与Dox同时给予GHRP-6可防止心肌纤维消耗和心室扩张，有效保留左心室收缩功能。GHRP-6还减轻了心脏外毒性，保持上皮器官完整性，抑制间质纤维化，并最终降低发病率和死亡率。从机制上讲，GHRP-6被证明可维持细胞抗氧化防御，上调促生存基因Bcl-2，并保持心肌细胞线粒体完整性。这些证据为GHRP-6在接受Dox治疗的患者中的临床应用开辟了潜在途径。
