Fibrosis is involved in the majority of cardiovascular diseases and is a key contributor to end-organ dysfunction. In the current study, the antifibrotic effects of recombinant human relaxin-2 (serelaxin; RLX) and/or the AT₂R agonist CGP42112 (CGP) were compared with those of the established AT₁R antagonist, candesartan cilexetil (CAND), in a high salt-induced cardiac fibrosis model. High salt (HS; 5%) for 8 weeks did not increase systolic blood pressure in male FVB/N mice, but CAND treatment alone significantly reduced systolic blood pressure from HS-induced levels. HS significantly increased cardiac interstitial fibrosis, which was reduced by either RLX and/or CGP, which were not additive under the current experimental conditions, while CAND failed to reduce HS-induced cardiac fibrosis. The antifibrotic effects induced by RLX and/or CGP were associated with reduced myofibroblast differentiation. Additionally, all treatments inhibited the HS-induced elevation in tissue inhibitor of matrix metalloproteinases-1, together with trends for increased MMP-13 expression, that collectively would favor collagen degradation. Furthermore, these antifibrotic effects were associated with reduced cardiac inflammation. Collectively, these results highlight that either RXFP1 or AT₂R stimulation represents novel therapeutic strategies to target fibrotic conditions, particularly in HS states that may be refractory to AT₁R blockade.

中文翻译：

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Serelaxin和AT ₂受体激动剂CGP42112在耐高坎地沙坦Cilexetil的高盐喂养小鼠中引起了类似的，非可加的，心脏抗纤维化作用

纤维化与大多数心血管疾病有关，并且是导致终末器官功能障碍的关键因素。在本研究中，将重组人松弛素2（serelaxin; RLX）和/或AT ₂ R激动剂CGP42112（CGP）的抗纤维化作用与已建立的AT ₁的抗纤维化作用进行了比较。在高盐诱导的心脏纤维化模型中，R拮抗剂坎地沙坦酯（CAND）。高盐（HS; 5％）持续8周并没有增加雄性FVB / N小鼠的收缩压，但是单独进行CAND治疗可以显着降低HS诱导水平的收缩压。HS显着增加了心脏间质纤维化，而RLX和/或CGP降低了心脏间质纤维化，在当前的实验条件下，RLX和/或CGP并没有加重，而CAND未能降低HS引起的心脏纤维化。RLX和/或CGP诱导的抗纤维化作用与成肌纤维细胞分化减少有关。另外，所有治疗均抑制了HS诱导的基质金属蛋白酶-1组织抑制剂的升高，以及MMP-13表达增加的趋势，这些趋势共同有利于胶原蛋白的降解。此外，这些抗纤维化作用与减少心脏炎症有关。这些结果共同表明，RXFP1或AT₂ R刺激代表了针对纤维化病况的新型治疗策略，尤其是在可能对AT ₁ R阻滞剂难治的HS状态下。