Jiang Jie, Li Meng-Yin, Wu Xue-Yuan, Ying Yi-Lun, Han Huan-Xing, Long Yi-Tao
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, China.
Nat Chem. 2023 Apr;15(4):578-586. doi: 10.1038/s41557-023-01139-8. Epub 2023 Feb 20.
The discovery of crosstalk effects on the renin-angiotensin system (RAS) is limited by the lack of approaches to quantitatively monitor, in real time, multiple components with subtle differences and short half-lives. Here we report a nanopore framework to quantitatively determine the effect of the hidden crosstalk between angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) on RAS. By developing an engineered aerolysin nanopore capable of single-amino-acid resolution, we show that the ACE can be selectively inhibited by ACE2 to prevent cleavage of angiotensin I, even when the concentration of ACE is more than 30-fold higher than that of ACE2. We also show that the activity of ACE2 for cleaving angiotensin peptides is clearly suppressed by the spike protein of SARS-CoV-2. This leads to the relaxation of ACE and the increased probability of accumulation of the principal effector angiotensin II. The spike protein of the SARS-CoV-2 Delta variant is demonstrated to have a much greater impact on the crosstalk than the wild type.
对肾素-血管紧张素系统（RAS）的串扰效应的发现受到限制，因为缺乏实时定量监测具有细微差异和短半衰期的多种成分的方法。在此，我们报告了一种纳米孔框架，用于定量确定血管紧张素转换酶（ACE）和血管紧张素转换酶2（ACE2）之间隐藏的串扰对RAS的影响。通过开发一种能够实现单氨基酸分辨率的工程化气单胞菌溶素纳米孔，我们表明ACE2可以选择性抑制ACE，以防止血管紧张素I的裂解，即使ACE的浓度比ACE2高30倍以上。我们还表明，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的刺突蛋白会明显抑制ACE2裂解血管紧张素肽的活性。这导致ACE的松弛以及主要效应物血管紧张素II积累概率的增加。事实证明，SARS-CoV-2 Delta变体的刺突蛋白对这种串扰的影响比野生型大得多。
