Antifibrotic effect of Ac-SDKP and angiotensin-converting enzyme inhibition in hypertension
Antifibrotic effect of Ac-SDKP and angiotensin-converting enzyme inhibition in hypertension
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DOI：
10.1097/00004872-200403000-00023
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发表时间：
2004-03-01
影响因子：
4.9
通讯作者：
Rhaleb, NE
中科院分区：
文献类型：
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作者：
Rasoul, S;Carretero, OA;Rhaleb, NE
目的N乙酰丝氨酰赖氨酰脯氨酸（Ac-SDKP）是一种天然的造血干细胞增殖抑制剂，主要由血管紧张素转换酶（ACE）降解。在体外，Ac-SDKP抑制心脏成纤维细胞的胶原蛋白产生;而在体内，它阻断高血压或心肌梗死（MI）大鼠左心室（LV）中的胶原蛋白沉积。此外，据报道，它可以预防和逆转MI大鼠LV中的巨噬细胞浸润。我们测试了这样的假设，即当Ac-SDKP以引起血浆浓度与ACE抑制后观察到的浓度相似的剂量输注时，它模拟了ACE抑制剂（ACEi）在心脏中的抗炎和抗纤维化作用，并且进一步地，这些作用不依赖于血压的变化。（1）对照，（2）Ang II（750 μ g/kg/天，s.c.），(3)（4）Ang II + Ac-SDKP（400 μ g/kg/天，s.c.），和（5）Ang II + Ac-SDKP（800 μ g/kg/天，s.c.）。我们测量了LV细胞增殖，炎症细胞浸润，细胞因子表达，肥大和fibrosis.Results血浆Ac-SDKP是五倍高的大鼠给予ACEi和四倍和十倍高的大鼠给予400和800 μ g/kg每天Ac-SDKP，分别。ACEi显著降低Ang II诱导的细胞增殖（Ki-67）、LV巨噬细胞/肥大细胞浸润、转化生长因子-β、结缔组织生长因子和胶原沉积，而不影响高血压、LV肥大或肌细胞横截面积，外源性Ac-SDKP可模拟上述效应（400 μ g/kg/d）升高血浆Ac-SDKP至与ACEi BP相似的水平，但ACEi或Ac-SDKP均未降低Ac-SDKP。ACEi在高血压中的炎症和抗纤维化作用与其血流动力学作用无关。(C)2004年利平科特威廉姆斯威尔金斯。
Objective N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a potent natural inhibitor of hematopoietic stem cell proliferation which is degraded mainly by angiotensin-converting enzyme (ACE). In vitro, Ac-SDKP inhibits collagen production by cardiac fibroblasts; while in vivo it blocks collagen deposition in the left ventricle (LV) of rats with hypertension or myocardial infarction (MI). In addition, it reportedly prevents and reverses macrophage infiltration in the LV of rats with MI. We tested the hypothesis that when Ac-SDKP is infused at doses that cause plasma concentrations similar to those observed after ACE inhibition, it mimics the anti-inflammatory and antifibrotic effects of ACE inhibitors (ACEi) in the heart, and, further, that these effects are independent of changes in blood pressure.Design and methods Rats were divided into five groups: (1) controls, (2) Ang II (750 mug/kg per day, s.c.), (3) Ang II + captopril (100 mg/kg per day in drinking water), (4) Ang II + Ac-SDKP (400 mug/kg per day, s.c.), and (5) Ang II + Ac-SDKP (800 mug/kg per day, s.c.). We measured LV cell proliferation, inflammatory cell infiltration, cytokine expression, hypertrophy and fibrosis.Results Plasma Ac-SDKP was five-fold higher in rats given ACEi and four- and ten-fold higher in rats given 400 and 800 mug/kg per day Ac-SDKP, respectively. ACEi significantly decreased Ang II-induced cell proliferation (Ki-67), LV macrophage/mast cell infiltration, transforming growth factor-beta, connective tissue growth factor and collagen deposition without affecting hypertension, LV hypertrophy or myocyte cross-sectional area, and these effects were mimicked by exogenous Ac-SDKP (400 mug/kg per day) which raised plasma Ac-SDKP to levels similar to ACEi BP was not decreased by either ACEi or Ac-SDKP.Conclusions We concluded that Ac-SDKP may be an important mediator of the anti-inflammatory and antifibrotic effects of ACEi in hypertension independent of its hemodynamic effects. (C) 2004 Lippincott Williams Wilkins.