Relaxin is a naturally occurring peptide hormone that mediates systemic hemodynamic and renal adaptive changes during pregnancy and abrogates aberrant scar tissue formation (fibrosis) in diverse pathogeneses. However, its efficacy relative to renin–angiotensin system blockade, the most effective antifibrotic strategy currently available, is not known. We compared the individual versus combined antifibrotic effects of serelaxin (a recombinant form of human gene-2 relaxin) and the angiotensin-converting enzyme inhibitor enalapril, in preventative (started before injury) and therapeutic (treatment of established fibrosis) strategies, in a mouse model of isoprenaline-induced cardiac injury (at 17 days). Changes in systolic blood pressure, organ hypertrophy, and tissue remodeling/fibrosis were assessed. Pretreatment with serelaxin (0.5 mg/kg per day via subcutaneous administration) alone reduced cardiac fibrosis to a greater extent than enalapril (200 mg/L via drinking water; equivalent to 48 mg/kg per day) alone (P<0.05 versus enalapril alone). Additionally, the combined effects of serelaxin and enalapril reduced cardiac fibrosis by at least 2-fold compared with enalapril alone, when administered preventatively or therapeutically; by suppressing transforming growth factor-β1 expression and phosphorylation of Smad2 (an intracellular regulator of transforming growth factor-β1 activity; both P<0.05 versus enalapril alone) to a greater extent. The effects of serelaxin were independent of blood pressure, while enalapril lowered systolic blood pressure in the model studied. These findings suggest that serelaxin alone and in combination with an angiotensin-converting enzyme inhibitor more effectively ameliorates fibrosis than angiotensin-converting enzyme inhibition alone in the diseased heart, in a clinically relevant experimental scenario.

译文

:松弛素是一种天然存在的肽激素,可在妊娠期间介导全身血液动力学和肾脏适应性变化,并消除多种病原体中异常的疤痕组织形成(纤维化)。但是,相对于肾素-血管紧张素系统阻滞剂(目前可用的最有效的抗纤维化策略)的疗效尚不清楚。我们在小鼠的预防(从受伤前开始)和治疗(已确立的纤维化治疗)策略中比较了Serelaxin(人类基因2松弛素的重组形式)和血管紧张素转化酶抑制剂依那普利的个体与联合抗纤维化作用。异丙肾上腺素诱发的心脏损伤模型(第17天)。评估收缩压,器官肥大和组织重塑/纤维化的变化。与单独使用依那普利(200 mg / L,通过饮用水;相当于每天48 mg / kg)相比,单独使用serelaxin(经皮下给药每天0.5 mg / kg)进行预处理可减少更大程度的心脏纤维化(与单独使用enalapril相比,P <0.05 )。此外,当预防性或治疗性给药时,与单独的依那普利相比,塞拉辛和依那普利的联合作用可使心脏纤维化减少至少两倍。通过更大程度地抑制转化生长因子-β1的表达和Smad2(转化生长因子-β1活性的细胞内调节剂; P <0.05与依那普利单独使用)的磷酸化来实现。 Serelaxin的作用与血压无关,而依那普利可降低所研究模型的收缩压。这些发现表明,在临床相关的实验情况下,与单独的血管紧张素转化酶抑制相比,单独的Serelaxin以及与血管紧张素转化酶抑制剂联合使用在患病心脏中比单独的血管紧张素转化酶抑制更有效地改善了纤维化。

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