Middleton Ryan C, Karpov Oleg A, Fournier Mario, Kreimer Simion, Mastali Mitra, Liu Weixin, Li Liang, Voelkel Norbert F, Van Eyk Jennifer E, Marbán Eduardo, Lewis Michael I
Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
Amsterdam University Medical Centers, Amsterdam, Netherlands.
PLoS One. 2025 May 12;20(5):e0321895. doi: 10.1371/journal.pone.0321895. eCollection 2025.
With pulmonary arterial hypertension (PAH), right ventricular (RV) function is a major determinant of survival. Despite current therapies, maladaptive changes ensue in the RV muscle of PAH patients, culminating in RV dysfunction and failure. The aims of the study were to evaluate the impact of intra-coronary (IC) cardiosphere-derived cells (CDCs) in attenuating the maladaptive pathobiology in the RV muscle and evaluating mechanisms underlying improvements in RV function.
Two groups of the Sugen/Hypoxia rat model of PAH, exhibiting significantly reduced RV function, via TAPSE measurements, received either intracoronary infusion of CDCs or PBS placebo. Immunohistochemistry methods were used to assess RV pathobiological changes. Additionally, advanced proteomics were employed to examine protein signaling pathways and upstream regulators.
RV muscle capillarity was significantly reduced in the PAH rats while RV muscle fibrosis was increased. IC CDCs significantly increased RV muscle capillarity back to levels noted in healthy rats and reduced RV free wall fibrosis. Further, a significant reduction in iNOS+ (M1) macrophages was also observed within the RV free wall in CDC-treated animals. Proteomic analysis of RV muscle in CDC- or PBS-treated PAH rats showed alterations in protein pathways related to inflammation, fibrosis, autophagy, cell vitality, and angiogenesis. These changes were consistent with putative coordination by a small number of key upstream regulators (MYC, TP53, HNF4A, TGFB1, and KRAS). TAPSE was significantly reduced in PBS-treated animals but was maintained at or above baseline levels in CDC-treated animals.
CDC therapy can significantly impact the maladaptive milieu of the RV myocardium in advanced PAH, by altering several pathobiological pathways. Such adjunctive therapy, in addition to those employed to reduce pulmonary vascular resistance, would be a great advance in managing RV failure, for which no effective current approved therapies exist.
在肺动脉高压（PAH）中，右心室（RV）功能是生存的主要决定因素。尽管有当前的治疗方法，但PAH患者的右心室肌肉仍会出现适应性不良变化，最终导致右心室功能障碍和衰竭。本研究的目的是评估冠状动脉内（IC）注射心脏球源细胞（CDC）对减轻右心室肌肉适应性不良病理生物学的影响，并评估右心室功能改善的潜在机制。
两组通过三尖瓣环平面收缩期位移（TAPSE）测量显示右心室功能显著降低的PAH Sugen/低氧大鼠模型，分别接受冠状动脉内注射CDC或PBS安慰剂。采用免疫组织化学方法评估右心室病理生物学变化。此外，运用先进的蛋白质组学技术检测蛋白质信号通路和上游调节因子。
PAH大鼠的右心室肌肉毛细血管密度显著降低，而右心室肌肉纤维化增加。冠状动脉内注射CDC可使右心室肌肉毛细血管密度显著恢复至健康大鼠水平，并减少右心室游离壁纤维化。此外，在接受CDC治疗的动物的右心室游离壁内，诱导型一氧化氮合酶阳性（M1）巨噬细胞也显著减少。对接受CDC或PBS治疗的PAH大鼠的右心室肌肉进行蛋白质组学分析，结果显示与炎症、纤维化、自噬、细胞活力和血管生成相关的蛋白质通路发生了改变。这些变化与少数关键上游调节因子（MYC、TP53、HNF4A、TGFB1和KRAS）的假定协调作用一致。在接受PBS治疗的动物中，TAPSE显著降低，但在接受CDC治疗的动物中，TAPSE维持在基线水平或以上。
CDC治疗可通过改变多种病理生物学途径，显著影响晚期PAH患者右心室心肌的适应性不良环境。除了用于降低肺血管阻力的治疗方法外，这种辅助治疗将是管理右心室衰竭的一大进步，目前尚无有效的获批治疗方法。
