EHP-101 alleviates angiotensin II-induced fibrosis and inflammation in mice
EHP-101 alleviates angiotensin II-induced fibrosis and inflammation in mice
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DOI：
10.1016/j.biopha.2021.112007
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发表时间：
2021-08-09
影响因子：
7.5
通讯作者：
Munoz, Eduardo
中科院分区：
文献类型：
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作者：
Garcia-Martin, Adela;Navarrete, Carmen;Munoz, Eduardo
一些大麻素具有抗炎和抗纤维化活性。 EHP-101 是新型非精神药物大麻二酚氨基醌 VCE-004.8 的口服脂质制剂，在博来霉素诱导的系统性硬化症小鼠模型中显示出抗纤维化活性。我们在此研究了 EHP-101 对血管紧张素 II 诱导的小鼠模型心脏和其他器官纤维化的影响。通过 α-SMA 表达检测到，VCE-004.8 抑制了 TGF β 和 Ang II 诱导的心脏成纤维细胞中的肌成纤维细胞分化。 VCE-004.8 还抑制 Ang II 诱导的心脏成纤维细胞中 ERK 1 + 2 磷酸化、NFAT 激活以及 IL1 beta、IL6、Col1A2 和 CCL2 的 mRNA 表达。注射Ang II的小鼠导致左心室、主动脉、真皮、肾和肺组织中胶原蛋白积聚；口服 EHP-101、Ajulemic Acid 和 Losartan 改善了这些表型。在心肌组织中，Ang II诱导T细胞和巨噬细胞的浸润以及胶原蛋白和腱蛋白C的积累； EHP-101 或氯沙坦治疗均可减少这些症状。心脏组织 RNA-Seq 分析揭示了炎症和纤维化途径治疗的相似转录组特征。然而，比较 EHP-101 与氯沙坦数据的基因集富集分析显示，仅由 EHP-101 修改的特定特征。具体来说，EHP-101 抑制 CDK1、TOP2A 和 MKi67 等基因的表达，这些基因受转录因子 E2 因子家族调节。这项研究表明口服 EHP-101 可以预防和抑制心脏炎症和纤维化。此外，EHP-101 还可抑制肾、肺和真皮纤维化。 EHP-101可以为治疗心脏纤维化和其他纤维化疾病提供新的机会。
Some cannabinoids showed anti-inflammatory and antifibrotic activities. EHP-101 is an oral lipidic formulation of the novel non-psychotropic cannabidiol aminoquinone VCE-004.8, which showed antifibrotic activity in murine models of systemic sclerosis induced by bleomycin. We herein examined the effect of EHP-101 on cardiac and other organ fibrosis in a mouse model induced by Angiotensin II. VCE-004.8 inhibited TGF beta- and Ang II induced myofibroblast differentiation in cardiac fibroblasts detected by alpha-SMA expression. VCE-004.8 also inhibited Ang II-induced ERK 1 + 2 phosphorylation, NFAT activation and mRNA expression of IL1 beta, IL6, Col1A2 and CCL2 in cardiac fibroblasts. Mice infused with Ang II resulted in collagen accumulation in left ventricle, aortic, dermal, renal and pulmonary tissues; oral administration of EHP-101, Ajulemic acid and Losartan improved these phenotypes. In myocardial tissue, Ang II induced infiltration of T cells and macrophages together with the accumulation of collagen and Tenascin C; those were all reduced by either EHP-101 or Losartan treatment. Cardiac tissue RNA-Seq analyses revealed a similar transcriptomic signature for both treatments for inflammatory and fibrotic pathways. However, the gene set enrichment analysis comparing data from EHP-101 vs Losartan showed specific hallmarks modified only by EHP-101. Specifically, EHP-101 inhibited the expression of genes such as CDK1, TOP2A and MKi67 that are regulated to the E2 factor family of transcription factors. This study suggests that the oral administration of EHP-101 prevents and inhibits cardiac inflammation and fibrosis. Furthermore, EHP-101 inhibits renal, pulmonary and dermal fibrosis. EHP-101 could offer new opportunities in the treatment of cardiac fibrosis and other fibrotic diseases.