BACKGROUND Cardiac hypertrophy is characterized by remodeling of the myocardium, which involves alterations in the ECM (extracellular matrix) and cardiomyocyte structure. These alterations critically contribute to impaired contractility and relaxation, ultimately leading to heart failure. Emerging evidence implicates that extracellular signaling molecules are critically involved in the pathogenesis of cardiac hypertrophy and remodeling. The immunophilin CyPA (cyclophilin A) has been identified as a potential culprit. In this study, we aimed to unravel the interplay between eCyPA (extracellular CyPA) and myocardial dysfunction and evaluate the therapeutic potential of inhibiting its extracellular accumulation to improve heart function. METHODS Employing a multidisciplinary approach encompassing in silico, in vitro, in vivo, and ex vivo experiments we studied a mouse model of cardiac hypertrophy and human heart specimen to decipher the interaction of CyPA and the cardiac microenvironment in highly relevant pre-/clinical settings. Myocardial expression of CyPA (immunohistology) and the inflammatory transcriptome (NanoString) was analyzed in human cardiac tissue derived from patients with nonischemic, noninflammatory congestive heart failure (n=187). These analyses were paralleled by a mouse model of Ang (angiotensin) II-induced heart failure, which was assessed by functional (echocardiography), structural (immunohistology, atomic force microscopy), and biomolecular (Raman spectroscopy) analyses. The effect of inhibiting eCyPA in the cardiac microenvironment was evaluated using a newly developed neutralizing anti-eCyPA monoclonal antibody. RESULTS We observed a significant accumulation of eCyPA in both human and murine-failing hearts. Importantly, higher eCyPA expression was associated with poor clinical outcomes in patients (P=0.043) and contractile dysfunction in mice (Pearson correlation coefficient, -0.73). Further, myocardial expression of eCyPA was critically associated with an increase in myocardial hypertrophy, inflammation, fibrosis, stiffness, and cardiac dysfunction in vivo. Antibody-based inhibition of eCyPA prevented (Ang II)-induced myocardial remodeling and dysfunction in mice. CONCLUSIONS Our study provides strong evidence of the pathogenic role of eCyPA in remodeling, myocardial stiffening, and dysfunction in heart failure. The findings suggest that antibody-based inhibition of eCyPA may offer a novel therapeutic strategy for nonischemic heart failure. Further research is needed to evaluate the translational potential of these interventions in human patients with cardiac hypertrophy.

中文翻译：

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靶向心脏微环境中的亲环蛋白 A 可保护衰竭心脏的心脏功能和结构。


背景技术心脏肥大的特征在于心肌重塑，这涉及ECM（细胞外基质）和心肌细胞结构的改变。这些改变严重影响收缩性和舒张性受损，最终导致心力衰竭。新的证据表明细胞外信号分子在心脏肥大和重塑的发病机制中发挥着重要作用。亲免素 CyPA（亲环素 A）已被确定为潜在的罪魁祸首。在本研究中，我们旨在揭示 eCyPA（细胞外 CyPA）与心肌功能障碍之间的相互作用，并评估抑制其细胞外积累以改善心脏功能的治疗潜力。方法采用包括计算机、体外、体内和离体实验在内的多学科方法，我们研究了心脏肥大的小鼠模型和人类心脏样本，以破译在高度相关的前/临床环境中 CyPA 和心脏微环境的相互作用。对来自非缺血性、非炎症性充血性心力衰竭患者 (n=187) 的人心脏组织中 CyPA（免疫组织学）和炎症转录组 (NanoString) 的心肌表达进行了分析。这些分析与 Ang（血管紧张素）II 诱导的心力衰竭小鼠模型并行，通过功能（超声心动图）、结构（免疫组织学、原子力显微镜）和生物分子（拉曼光谱）分析进行评估。使用新开发的中和性抗 eCyPA 单克隆抗体评估了在心脏微环境中抑制 eCyPA 的效果。结果我们观察到人类和小鼠衰竭心脏中 eCyPA 显着积累。 重要的是，较高的 eCyPA 表达与患者不良临床结果 (P=0.043) 和小鼠收缩功能障碍相关 (Pearson 相关系数，-0.73)。此外，eCyPA 的心肌表达与体内心肌肥大、炎症、纤维化、僵硬和心功能障碍的增加密切相关。基于抗体的 eCyPA 抑制可预防 (Ang II) 诱导的小鼠心肌重塑和功能障碍。结论 我们的研究为 eCyPA 在心力衰竭的重构、心肌僵硬和功能障碍中的致病作用提供了有力的证据。研究结果表明，基于抗体的 eCyPA 抑制可能为非缺血性心力衰竭提供一种新的治疗策略。需要进一步的研究来评估这些干预措施对人类心脏肥大患者的转化潜力。