Wu Chunxue, Chen Yuhong, Zhou Pan, Hu Zhenjie
Department of Critical Care Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Intensive Care Unit of Emergency Department, Neurology Branch of Cangzhou Central Hospital, Cangzhou, China.
Ann Transl Med. 2023 Jan 15;11(1):13. doi: 10.21037/atm-22-6016. Epub 2023 Jan 10.
Sepsis-induced cardiac dysfunction (SICD) is a common complication of sepsis and contributes to mortality and the complexity of management in patients with sepsis. Recombinant human angiotensin-converting enzyme 2 (rhACE2) has been reported to protect the heart from injury and dysfunction in conditions which involve increased angiotensin II (Ang II). In this study, we aimed to detect the effects of rhACE2 on SICD.
A SICD model was developed in male C57/B6 mice by lipopolysaccharide (LPS) intraperitoneal injection. When cardiac dysfunction was confirmed by echocardiography 3 hours after LPS administration, mice were treated with either saline, rhACE2, or rhACE2 + A779. All mice received echocardiographic examination at 6 hours after LPS injection and then were sacrificed for serum and myocardial tissues collection. Angiotensin, cardiac troponin I (cTnI), and inflammatory markers in serum were measured. Histopathology features were examined by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining to evaluate structure injury and cell pyroptosis rate in heart tissue respectively. Pyroptosis-related proteins and signaling pathways involved in nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in heart tissue were investigated by western blot (WB).
RhACE2 relieved myocardial injury and improved cardiac function in mice with SICD accompanied by decrease of Ang II and increase of angiotensin 1-7 (Ang 1-7) in serum. RhACE2 diminished activation of NLRP3 inflammasome, inflammatory response, and cell pyroptosis induced by LPS. In addition, rhACE2 partly inhibited activation of nuclear factor κB (NF-κB), the p38 mitogen-activated protein kinase (MAPK) pathway, and promoted activation of the AMP-activated protein kinase-α1 (AMPK-α1) pathway in heart tissue. Administration of A779 offset the inhibitive effects of rhACE2 on NLRP3 expression and protective role on cardiac injury and dysfunction in mice with SICD.
RhACE2 plays a protective role in SICD, ameliorating cardiac injury and dysfunction through NF-κB, p38 MAPK, and the AMPK-α1/NLRP3 inflammasome pathway dependent on converting Ang II to Ang 1-7.
脓毒症诱导的心脏功能障碍（SICD）是脓毒症常见的并发症，会增加脓毒症患者的死亡率及管理复杂性。据报道，重组人血管紧张素转换酶2（rhACE2）在血管紧张素II（Ang II）增加的情况下可保护心脏免受损伤及功能障碍。在本研究中，我们旨在检测rhACE2对SICD的影响。
通过腹腔注射脂多糖（LPS）在雄性C57/B6小鼠中建立SICD模型。在给予LPS 3小时后通过超声心动图确认心脏功能障碍时，将小鼠分别用生理盐水、rhACE2或rhACE2 + A779进行处理。所有小鼠在注射LPS后6小时接受超声心动图检查，然后处死以收集血清和心肌组织。检测血清中的血管紧张素、心肌肌钙蛋白I（cTnI）和炎症标志物。通过苏木精和伊红（HE）染色及末端脱氧核苷酸转移酶（TdT）介导的dUTP缺口末端标记（TUNEL）染色检查组织病理学特征，分别评估心脏组织的结构损伤和细胞焦亡率。通过蛋白质免疫印迹法（WB）研究心脏组织中与焦亡相关的蛋白以及参与含核苷酸结合寡聚化结构域样受体家族pyrin结构域3（NLRP3）炎性小体激活的信号通路。
RhACE2可减轻SICD小鼠的心肌损伤并改善心脏功能，同时血清中Ang II减少而血管紧张素1 - 7（Ang 1 - 7）增加。RhACE2可减少LPS诱导的NLRP3炎性小体激活、炎症反应和细胞焦亡。此外，rhACE2可部分抑制心脏组织中核因子κB（NF - κB）、p38丝裂原活化蛋白激酶（MAPK）通路的激活，并促进AMP活化蛋白激酶 - α1（AMPK - α1）通路的激活。给予A779可抵消rhACE2对SICD小鼠NLRP3表达的抑制作用及其对心脏损伤和功能障碍的保护作用。
RhACE2在SICD中发挥保护作用，通过依赖于将Ang II转化为Ang 1 - 7的NF - κB、p38 MAPK和AMPK - α1/NLRP3炎性小体通路改善心脏损伤和功能障碍。
