Martin Brian, Gabris-Weber Beth Ann, Reddy Rajiv, Romero Guillermo, Chattopadhyay Ansuman, Salama Guy
Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States of America.
School of Medicine, Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, PA, United States of America.
PLoS One. 2018 Jan 18;13(1):e0190935. doi: 10.1371/journal.pone.0190935. eCollection 2018.
'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 recent clinical trials, Relaxin-therapy for 2-days could reduce mortality by 37% at 180-days post-treatment, in patients with acute decompensated HF. Relaxin's short life-span (hours) but long-lasting protective actions led us to test the hypothesis that relaxin acts at a genomic level to reverse maladaptive remodeling in aging and HF.
Young (9-month) and aged (24-month), male and female F-344/Brown Norway rats were treated with relaxin (0.4 mg/kg/day) for 2-weeks delivered by subcutaneous osmotic mini-pumps or with sodium acetate (controls). The genomic effects of aging and relaxin were evaluated by extracting RNA from the left ventricles and analyzing genomic changes by RNA-sequencing, Ingenuity Pathway Analysis, MetaCore and tissue immunohistochemistry. We found that aging promotes a native inflammatory response with distinct sex-differences and relaxin suppresses transcription of multiple genes and signaling pathways associated with inflammation and HF in both genders. In addition, aging significantly increased: macrophage infiltration and atrial natriuretic peptide levels in female ventricles, and activation of the complement cascade, whereas relaxin reversed these age-related effects.
These data support the hypothesis that relaxin alters gene transcription and suppresses inflammatory pathways and genes associated with HF and aging. Relaxin's suppression of inflammation and fibrosis supports its potential as a therapy for cardiovascular and inflammation-related diseases, such as HF, AF and diabetes.
“健康”衰老会引发心脏结构和功能的变化，包括适应性不良的电重构、纤维化和炎症，这会降低心力衰竭（HF）和心房颤动（AF）等心血管疾病的发病阈值。尽管近期临床试验结果不一，但对于急性失代偿性HF患者，为期2天的松弛素治疗可使治疗后180天时的死亡率降低37%。松弛素的短半衰期（数小时）但持久的保护作用促使我们检验这样一个假设，即松弛素在基因组水平发挥作用，以逆转衰老和HF过程中的适应性不良重构。
将年轻（9个月）和老年（24个月）的雄性和雌性F-344/棕色挪威大鼠，通过皮下渗透微型泵给予松弛素（0.4mg/kg/天）治疗2周，或给予醋酸钠（对照组）。通过从左心室提取RNA并通过RNA测序、 Ingenuity通路分析、MetaCore和组织免疫组化分析基因组变化，评估衰老和松弛素的基因组效应。我们发现，衰老会引发具有明显性别差异的天然炎症反应，而松弛素可抑制与炎症和HF相关的多个基因及信号通路的转录。此外，衰老显著增加了：雌性心室中的巨噬细胞浸润和心钠素水平，以及补体级联的激活，而松弛素可逆转这些与年龄相关的效应。
这些数据支持了这样一个假设，即松弛素可改变基因转录并抑制与HF和衰老相关的炎症通路及基因。松弛素对炎症和纤维化的抑制作用支持了其作为心血管和炎症相关疾病（如HF、AF和糖尿病）治疗方法的潜力。
