Cavasin Maria A, Rhaleb Nour-Eddine, Yang Xiao-Ping, Carretero Oscar A
Hypertension and Vascular Research Division, Henry Ford Health System, 2799 West Grand Blvd, E&R 7115, Detroit, Mich 4820, USA.
Hypertension. 2004 May;43(5):1140-5. doi: 10.1161/01.HYP.0000126172.01673.84. Epub 2004 Mar 22.
N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a ubiquitous tetrapeptide hydrolyzed almost exclusively by angiotensin-converting enzyme (ACE). Chronic treatment with Ac-SDKP decreases cardiac and renal fibrosis and inflammatory cell infiltration in hypertensive rats. However, very little is known about endogenous synthesis of Ac-SDKP, except that thymosin-beta4 may be the most likely precursor. Two enzymes are potentially able to release Ac-SDKP from thymosin-beta4: prolyl oligopeptidase (POP) and endoproteinase asp-N. POP is widely present and active in several tissues and biological fluids, whereas endoproteinase asp-N appears to be lacking in mammals. Therefore, we hypothesized that POP is the main enzyme involved in synthesizing the antifibrotic peptide Ac-SDKP. We investigated in vitro and in vivo production of Ac-SDKP. Using kidney cortex homogenates, we observed that Ac-SDKP was generated in a time-dependent manner in the presence of exogenous thymosin-beta4, and this generation was significantly inhibited by several POP inhibitors (POPi), Z-prolyl-prolinal, Fmoc-prolyl-pyrrolidine-2-nitrile, and S17092. Long-term administration of S17092 in rats significantly decreased endogenous levels of Ac-SDKP in the plasma (from 1.76+/-0.2 to 1.01+/-0.1 nM), heart (from 2.31+/-0.21 to 0.83+/-0.09 pmol/mg protein), and kidneys (from 5.62+/-0.34 to 2.86+/-0.76 pmol/mg protein). As expected, ACE inhibitors significantly increased endogenous levels of Ac-SDKP in the plasma, heart, and kidney, whereas coadministration of POPi prevented this increase. We concluded that POP is the main enzyme responsible for synthesis of the antifibrotic peptide Ac-SDKP.
N-乙酰基-丝氨酰-天冬氨酰-赖氨酰-脯氨酸（Ac-SDKP）是一种普遍存在的四肽，几乎仅由血管紧张素转换酶（ACE）水解。用Ac-SDKP长期治疗可减少高血压大鼠的心脏和肾脏纤维化以及炎性细胞浸润。然而，除了胸腺素β4可能是最有可能的前体之外，关于Ac-SDKP的内源性合成知之甚少。有两种酶可能能够从胸腺素β4释放出Ac-SDKP：脯氨酰寡肽酶（POP）和天冬氨酸内肽酶N。POP广泛存在于多种组织和生物体液中并具有活性，而天冬氨酸内肽酶N在哺乳动物中似乎不存在。因此，我们推测POP是参与合成抗纤维化肽Ac-SDKP的主要酶。我们研究了Ac-SDKP的体外和体内生成情况。使用肾皮质匀浆，我们观察到在外源胸腺素β4存在的情况下，Ac-SDKP以时间依赖性方式生成，并且这种生成受到几种POP抑制剂（POPi）、Z-脯氨酰-脯氨醛、芴甲氧羰基-脯氨酰-吡咯烷-2-腈和S17092的显著抑制。在大鼠中长期给予S17092可显著降低血浆（从1.76±0.2降至1.01±0.1 nM）、心脏（从2.31±0.21降至0.83±0.09 pmol/mg蛋白质）和肾脏（从5.62±0.34降至2.86±0.76 pmol/mg蛋白质）中Ac-SDKP的内源性水平。正如预期的那样，ACE抑制剂显著提高了血浆、心脏和肾脏中Ac-SDKP的内源性水平，而同时给予POPi可阻止这种升高。我们得出结论，POP是负责合成抗纤维化肽Ac-SDKP的主要酶。
