INSERM U1167-RID-AGE, CHU Lille, FHU-REMOD-VHF (A.T., M.F., M.B., N.L., P.d.G., S.P., M.C., O.B., P.A., C.B., F.P.).
Institut Pasteur de Lille, Université de Lille, France. Inserm U1096, FHU-REMOD-VHF, Normandie University, University of Rouen, France (P.M., V.R.).
Circ Heart Fail. 2018 Jun;11(6):e004838. doi: 10.1161/CIRCHEARTFAILURE.117.004838.
Left ventricular remodeling (LVR) after myocardial infarction is associated with an increased risk of heart failure and death. In spite of a modern therapeutic approach, LVR remains relatively frequent and difficult to predict in clinical practice. Our aim was to identify new biomarkers of LVR and understand their involvement in its development.
Proteomic analysis of plasma from the REVE-2 study (Remodelage Ventriculaire)-a study dedicated to the analysis of LVR which included 246 patients after a first anterior myocardial infarction-identified increased plasma levels of CLU (clusterin) in patients with high LVR. We used a rat model of myocardial infarction to analyze CLU expression in the LV and found a significant increase that was correlated with LVR parameters. We found increased CLU expression and secretion in primary cultures of rat neonate cardiomyocytes hypertrophied by isoproterenol. Silencing of CLU in hypertrophied neonate cardiomyocytes induced a significant decrease in cell size, ANP (atrial natriuretic peptide), and BNP (B-type natriuretic peptide) expression, associated with a decreased ERK (extracellular signal-regulated kinase) 1/2 activity, suggesting a prohypertrophic role of CLU. We then confirmed a significant increase of both intracellular p-CLU (precursor form of CLU) and m-CLU (mature form of CLU) in failing human hearts. Finally, the circulating levels of CLU (secreted form) were increased in patients with chronic heart failure who died from cardiovascular cause during a 3-year follow-up (n=99) compared with survivors (n=99).
Our results show for the first time that plasma CLU levels are associated with LVR post-myocardial infarction, have in part a cardiac origin, and are a predictor of early death in heart failure patients.
心肌梗死后左心室重构（LVR）与心力衰竭和死亡风险增加相关。尽管采用了现代治疗方法，LVR 在临床实践中仍然相对常见且难以预测。我们的目的是确定 LVR 的新生物标志物，并了解其在其发展中的作用。
对来自 REVE-2 研究（心室重构）的血浆进行蛋白质组学分析-这项研究专门用于分析包括 246 例首次前壁心肌梗死后的 LVR-发现 LVR 较高的患者血浆中 CLU（簇蛋白）水平升高。我们使用心肌梗死大鼠模型分析 LV 中的 CLU 表达，发现其表达显著增加，且与 LVR 参数相关。我们发现，异丙肾上腺素诱导的大鼠原代培养新生心肌细胞肥大时 CLU 表达和分泌增加。在肥大的新生心肌细胞中沉默 CLU 可显著降低细胞大小、ANP（心房利钠肽）和 BNP（B 型利钠肽）的表达，同时降低 ERK（细胞外信号调节激酶）1/2 的活性，表明 CLU 具有促肥大作用。然后，我们在衰竭的人心肌中证实了细胞内 p-CLU（CLU 的前体形式）和 m-CLU（CLU 的成熟形式）的含量均显著增加。最后，在 3 年随访期间因心血管原因死亡的慢性心力衰竭患者（n=99）与幸存者（n=99）相比，循环 CLU（分泌形式）水平升高。
我们的研究结果首次表明，血浆 CLU 水平与心肌梗死后的 LVR 相关，部分源于心脏，且是心力衰竭患者早期死亡的预测因子。
