Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, United States.
Department of Medicine, Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, PA, United States.
Vitam Horm. 2021;115:419-448. doi: 10.1016/bs.vh.2020.12.017. Epub 2021 Feb 18.
"Healthy" aging drives structural and functional changes in the heart including maladaptive electrical remodeling, fibrosis and inflammation, which lower the threshold for cardiovascular diseases such as heart failure (HF) and atrial fibrillation (AF). Despite mixed results in clinical trials, Relaxin-therapy for 2-days reduced mortality by 37% at 180-days post-treatment, in patients with acute decompensated HF. Relaxin's short lifespan (2-3h) but long-lasting protective actions suggested that relaxin acts at a genomic level to reverse maladaptive remodeling in AF, HF and aging. Our recent studies showed that a 2-week treatment with Relaxin (0.4mg/kg/day) of aged (24months old F-344 rats) increases the expression of voltage-gated Na channels (mRNA, Nav1.5 and I), connexin-43, abrogates inflammatory and immune responses and reverses myocardial fibrosis and cellular hypertrophy of the aged hearts. Relaxin acts directly at a wide range of cell types in the cardiovascular system that express its cognate GPCR receptor, RXFP1. RNA-seq analysis of young and aged hearts with and without Relaxin treatment revealed that "normal" aging altered the expression of ~10% of genes expressed in the ventricles, including: ion channels, components of fibrosis, hemodynamic biomarkers, immune and inflammatory responses which were reversed by Relaxin. The extensive cardiovascular remodeling caused by Relaxin was mediated through the activation of the Wnt/β-catenin signaling pathway which was otherwise suppressed by in adult cardiomyocytes intracellular by cytosolic Dickkopf1 (Dkk1). Wnt/β-catenin signaling is a mechanism that can explain the pleiotropic actions of Relaxin and the marked reversal of genomic changes that occur in aged hearts.
“健康”衰老会导致心脏的结构和功能发生变化，包括适应性电重构、纤维化和炎症，从而降低心力衰竭（HF）和心房颤动（AF）等心血管疾病的发病阈值。尽管临床试验结果喜忧参半，但在急性失代偿性 HF 患者中，Relaxin 治疗 2 天可使 180 天后的死亡率降低 37%。Relaxin 的短半衰期（2-3 小时）但持久的保护作用表明，Relaxin 作用于基因组水平，可逆转 AF、HF 和衰老中的适应性重构。我们最近的研究表明，用 Relaxin（0.4mg/kg/天）治疗 2 周可增加老年（24 个月大的 F-344 大鼠）心脏电压门控 Na 通道（mRNA、Nav1.5 和 I）、连接蛋白-43 的表达，消除炎症和免疫反应，并逆转老年心脏的心肌纤维化和细胞肥大。Relaxin 直接作用于心血管系统中广泛表达其同源 GPCR 受体 RXFP1 的多种细胞类型。对有和没有 Relaxin 治疗的年轻和老年心脏进行 RNA-seq 分析表明，“正常”衰老改变了心室中约 10%表达基因的表达，包括：离子通道、纤维化成分、血流动力学生物标志物、免疫和炎症反应，这些反应均可被 Relaxin 逆转。Relaxin 引起的广泛心血管重构是通过激活 Wnt/β-catenin 信号通路介导的，而该通路在成年心肌细胞中被细胞质 Dickkopf1（Dkk1）抑制。Wnt/β-catenin 信号通路是一种可以解释 Relaxin 的多效作用和衰老心脏中发生的基因组变化明显逆转的机制。
