Chattopadhyay Saurabh, Kessler Sean P, Colucci Juliana Almada, Yamashita Michifumi, Senanayake Preenie deS, Sen Ganes C
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
PLoS One. 2014 Jan 27;9(1):e87484. doi: 10.1371/journal.pone.0087484. eCollection 2014.
Angiotensin-converting enzyme (ACE) regulates normal blood pressure and fluid homeostasis through its action in the renin-angiotensin-system (RAS). Ace-/- mice are smaller in size, have low blood pressure and defective kidney structure and functions. All of these defects are cured by transgenic expression of somatic ACE (sACE) in vascular endothelial cells of Ace-/- mice. sACE is expressed on the surface of vascular endothelial cells and undergoes a natural cleavage secretion process to generate a soluble form in the body fluids. Both the tissue-bound and the soluble forms of ACE are enzymatically active, and generate the vasoactive octapeptide Angiotensin II (Ang II) with equal efficiency. To assess the relative physiological roles of the secreted and the cell-bound forms of ACE, we expressed, in the vascular endothelial cells of Ace-/- mice, the ectodomain of sACE, which corresponded to only the secreted form of ACE. Our results demonstrated that the secreted form of ACE could normalize kidney functions and RAS integrity, growth and development of Ace-/- mice, but not their blood pressure. This study clearly demonstrates that the secreted form of ACE cannot replace the tissue-bound ACE for maintaining normal blood pressure; a suitable balance between the tissue-bound and the soluble forms of ACE is essential for maintaining all physiological functions of ACE.
血管紧张素转换酶（ACE）通过其在肾素-血管紧张素系统（RAS）中的作用来调节正常血压和体液平衡。ACE基因敲除小鼠体型较小，血压低，肾脏结构和功能存在缺陷。在ACE基因敲除小鼠的血管内皮细胞中通过转基因表达体细胞ACE（sACE）可治愈所有这些缺陷。sACE在血管内皮细胞表面表达，并经历自然的切割分泌过程，在体液中产生可溶性形式。ACE的组织结合形式和可溶性形式都具有酶活性，并且以相同效率产生血管活性八肽血管紧张素II（Ang II）。为了评估ACE分泌形式和细胞结合形式的相对生理作用，我们在ACE基因敲除小鼠的血管内皮细胞中表达了sACE的胞外结构域，其仅对应于ACE的分泌形式。我们的结果表明，ACE的分泌形式可以使ACE基因敲除小鼠的肾功能、RAS完整性、生长和发育正常化，但不能使其血压正常化。这项研究清楚地表明，ACE的分泌形式不能替代组织结合型ACE来维持正常血压；ACE组织结合形式和可溶性形式之间的适当平衡对于维持ACE的所有生理功能至关重要。
