Abudukeremu Asimuguli, Aikemu Ainiwaer, Yang Tao, Fang Lei, Aihemaitituoheti Adilai, Zhang Yupeng, Shanahaiti Daliya, Nijiati Yiliyaer
Central Laboratory of Xinjiang Medical University, Urumqi, China.
College of Pharmacy, Xinjiang Medical University, Urumqi, China.
Front Microbiol. 2024 Aug 23;15:1412502. doi: 10.3389/fmicb.2024.1412502. eCollection 2024.
Pulmonary artery hypertension (PAH) poses a significant challenge due to its limited therapeutic options and high mortality rates. The ACE2-Ang-(1-7)-Mas axis plays a pivotal role in regulating blood pressure and inhibiting myocardial remodeling. However, the precise mechanistic links between the ACE2-Ang-(1-7)-Mas axis and PAH remain poorly understood. This study aimed to elucidate the involvement of the ACE2-Ang-(1-7)-Mas axis in the development of PAH.
PAH was induced in mice using Sugen5416/hypoxia, PAAT/PET ratio and PA were detected using cardiac ultrasound; inflammation related factors such as MCP-1, TNF, IL-10and IL-12p70 were detected in intestines using cytometric bead array (CBA) kits; histopathological and morphological changes in lung and intestinal tissues were assessed via HE staining and Masson staining to evaluate the progression of PAH. Immunohistochemistry and western blotting were employed to determine the expression levels of two tight junction proteins, occludin and ZO-1, in intestinal tissues. Additionally, 16rRNA sequencing and non-targeted metabolomics by LC-MS/MS techniques were utilized to investigate the impact of the ACE2-Ang-(1-7)-Mas axis on microbial diversity and metabolomics of intestinal contents.
Activation of the ACE2-Ang-(1-7)-Mas axis improves heart function, reduces intestines inflammatory factors and ameliorates pathological and histological alterations in SuHx mice. This activation notably upregulated the expression of occludin and ZO-1 proteins in intestinal tissues and promoted the proliferation of SCFA-producing bacteria genera, such as . Furthermore, it enhanced the abundance of beneficial metabolites, including tryptophan and butyric acid.
The findings suggest that modulation of the ACE2-Ang-(1-7)-Mas axis can alleviate PAH by regulating intestinal microbes and metabolites. These results highlight the potential of the ACE2-Ang-(1-7)-Mas axis as a promising therapeutic target for clinical management of PAH.
肺动脉高压（PAH）因其治疗选择有限和死亡率高而构成重大挑战。血管紧张素转换酶2-血管紧张素-(1-7)-Mas轴在调节血压和抑制心肌重塑中起关键作用。然而，ACE2-血管紧张素-(1-7)-Mas轴与PAH之间的确切机制联系仍知之甚少。本研究旨在阐明ACE2-血管紧张素-(1-7)-Mas轴在PAH发生发展中的作用。
使用Sugen5416/低氧诱导小鼠发生PAH，采用心脏超声检测肺动脉面积与主动脉面积比值（PAAT/PET ratio）和肺动脉（PA）；使用细胞计数珠阵列（CBA）试剂盒检测肠道中单核细胞趋化蛋白-1（MCP-1）、肿瘤坏死因子（TNF）、白细胞介素-10（IL-10）和白细胞介素-12p70等炎症相关因子；通过苏木精-伊红（HE）染色和马松（Masson）染色评估肺和肠道组织的组织病理学和形态学变化，以评估PAH的进展。采用免疫组织化学和蛋白质免疫印迹法测定肠道组织中两种紧密连接蛋白闭合蛋白（occludin）和紧密连接蛋白1（ZO-1）的表达水平。此外，利用16S核糖体RNA（rRNA）测序和液相色谱-串联质谱（LC-MS/MS）技术进行非靶向代谢组学分析，以研究ACE2-血管紧张素-(1-7)-Mas轴对肠道内容物微生物多样性和代谢组学的影响。
激活ACE2-血管紧张素-(1-7)-Mas轴可改善心脏功能，降低肠道炎症因子水平，并改善SuHx小鼠的病理和组织学改变。这种激活显著上调了肠道组织中occludin和ZO-1蛋白的表达，并促进了短链脂肪酸产生菌属的增殖，如 。此外，它还增加了有益代谢物的丰度，包括色氨酸和丁酸。
研究结果表明，调节ACE2-血管紧张素-(1-7)-Mas轴可通过调节肠道微生物和代谢物来减轻PAH。这些结果突出了ACE2-血管紧张素-(1-7)-Mas轴作为PAH临床治疗有前景的治疗靶点的潜力。
