From the Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona. Spain (E.M.-M., J.I., A.F.-C., N.L.-A.).
INSERM UMRS 1138 Team 1, Centre de Recherche des Cordeliers, University Pierre and Marie Curie, Paris, France (E.M.M., M.B., F.J.).
Hypertension. 2019 Mar;73(3):602-611. doi: 10.1161/HYPERTENSIONAHA.118.11874.
Myocardial fibrosis is a main contributor to the development of heart failure (HF). CT-1 (cardiotrophin-1) and Gal-3 (galectin-3) are increased in HF and associated with myocardial fibrosis. The aim of this study is to analyze whether CT-1 regulates Gal-3. Proteomic analysis revealed that Gal-3 was upregulated by CT-1 in human cardiac fibroblasts in parallel with other profibrotic and proinflammatory markers. CT-1 upregulation of Gal-3 was mediated by ERK (extracellular signal-regulated kinase) 1/2 and Stat-3 (signal transducer and activator of transcription 3) pathways. Male Wistar rats and B6CBAF1 mice treated with CT-1 (20 µg/kg per day) presented higher cardiac Gal-3 levels and myocardial fibrosis. In CT-1-treated rats, direct correlations were found between cardiac CT-1 and Gal-3 levels, as well as between Gal-3 and perivascular fibrosis. Gal-3 genetic disruption in human cardiac fibroblasts and pharmacological Gal-3 inhibition in mice prevented the profibrotic and proinflammatory effects of CT-1. Dahl salt-sensitive hypertensive rats with diastolic dysfunction showed increased cardiac CT-1 and Gal-3 expression together with cardiac fibrosis and inflammation. CT-1 and Gal-3 directly correlated with myocardial fibrosis. In HF patients, myocardial and plasma CT-1 and Gal-3 were increased and directly correlated. In addition, HF patients with high CT-1 and Gal-3 plasma levels presented an increased risk of cardiovascular death. Our data suggest that CT-1 upregulates Gal-3 which, in turn, mediates the proinflammatory and profibrotic myocardial effects of CT-1. The elevation of both molecules in HF patients identifies a subgroup of patients with a higher risk of cardiovascular mortality. The CT-1/Gal-3 axis emerges as a candidate therapeutic target and a potential prognostic biomarker in HF.
心肌纤维化是心力衰竭（HF）发展的主要原因。 CT-1（心肌营养素-1）和 Gal-3（半乳糖凝集素-3）在 HF 中增加，并与心肌纤维化相关。本研究旨在分析 CT-1 是否调节 Gal-3。蛋白质组学分析显示，CT-1 在人心肌成纤维细胞中与其他促纤维化和促炎标志物平行上调 Gal-3。 CT-1 上调 Gal-3 是通过 ERK（细胞外信号调节激酶）1/2 和 Stat-3（信号转导和转录激活因子 3）途径介导的。用 CT-1（每天 20µg/kg）治疗的雄性 Wistar 大鼠和 B6CBAF1 小鼠表现出更高的心脏 Gal-3 水平和心肌纤维化。在 CT-1 治疗的大鼠中，心脏 CT-1 和 Gal-3 水平之间以及 Gal-3 和血管周围纤维化之间存在直接相关性。在人心肌成纤维细胞中敲除 Gal-3 基因和在小鼠中抑制 Gal-3 药理学可防止 CT-1 的促纤维化和促炎作用。伴有舒张功能障碍的 Dahl 盐敏感高血压大鼠表现出心脏 CT-1 和 Gal-3 表达增加，以及心肌纤维化和炎症。 CT-1 和 Gal-3 与心肌纤维化直接相关。在 HF 患者中，心肌和血浆 CT-1 和 Gal-3 增加且直接相关。此外，HF 患者中具有高 CT-1 和 Gal-3 血浆水平的患者心血管死亡风险增加。我们的数据表明，CT-1 上调 Gal-3，而 Gal-3 又介导 CT-1 的促炎和促纤维化心肌作用。 HF 患者中这两种分子的升高确定了具有更高心血管死亡率风险的患者亚组。 CT-1/Gal-3 轴作为 HF 中的候选治疗靶标和潜在的预后生物标志物出现。
