Ac-SDKP reverses cardiac fibrosis in rats with renovascular hypertension
Ac-SDKP reverses cardiac fibrosis in rats with renovascular hypertension
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DOI：
10.1161/01.hyp.0000100423.24330.96
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发表时间：
2003-12-01
期刊：
影响因子：
8.3
通讯作者：
Rhaleb, NE
中科院分区：
文献类型：
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作者：
Peng, HM;Carretero, OA;Rhaleb, NE
N-乙酰-丝氨酸-天冬氨酰-赖氨酸(Ac-SDKP)是血管紧张素转换酶(ACE)N端活性部位的天然底物。我们先前报道了Ac-SDKP预防肾血管性或醛固酮-盐性高血压大鼠的心脏纤维化。然而，尚不清楚Ac-SDKP是否逆转高血压患者的心脏纤维化，也不清楚其中涉及的机制(S)。在本研究中，我们验证了Ac-SDKP逆转高血压诱导的心肌纤维化涉及转化生长因子-β(TGF-β)和/或结缔组织生长因子(CTGF)减少的假设。在2肾1夹(2K-1C)高血压大鼠，在建立高血压和心肌纤维化模型后8周开始每日皮下注射Ac-SDKP 400或800 mg/kg，并持续8周。夹闭后8周和16周，2K-1C+赋形剂组大鼠左室心肌胶原含量与假手术组相似，但高于假手术组(P<；0.05)。每日400和800μg/kg的Ac-SDKP使血浆Ac-SdKP分别增加2倍和5倍，并呈剂量依赖关系逆转LV胶原的增加。Ac-SDKP逆转LV纤维化的机制似乎不依赖于Ac-SDKP对ACE的抑制，因为我们发现不同剂量的Ac-SDKP不影响血压对外源性血管紧张素I或缓激肽的反应。然而，与2K-1C加赋形剂组相比，AC-SDKP逆转了大鼠左室转化生长因子β和结缔组织生长因子的增加(P<；0.005)。我们的结论是，在高血压患者，Ac-SDKP逆转了心脏纤维化，可能部分是由于心脏中转化生长因子-β和CTGF的减少。
N- acetyl- seryl- aspartyl- lysyl- proline ( Ac- SDKP) is a natural substrate for the N- terminal active site of angiotensin- converting enzyme ( ACE). We previously reported that Ac- SDKP prevented cardiac fibrosis in rats with renovascular or aldosterone- salt hypertension. However, it is not clear whether Ac- SDKP reverses cardiac fibrosis in hypertension, nor the mechanism( s) involved. In the present study, we tested the hypothesis that Ac- SDKP reversal of hypertension- induced cardiac fibrosis involves a decrease in transforming growth factor- beta ( TGF-beta) and/ or connective tissue growth factor ( CTGF). In 2- kidney, 1- clip ( 2K- 1C) hypertensive rats, Ac- SDKP at 400 or 800 mu g/ kg per day SC was started 8 weeks after hypertension and cardiac fibrosis were established and was continued for 8 weeks. Left ventricular ( LV) collagen in rats with 2K- 1C plus vehicle at 8 and 16 weeks after clipping was similar but higher than in the sham group ( P < 0.05). Ac- SDKP at 400 and 800 μ g/ kg per day, which increased plasma Ac- SDKP 2- and 5- fold, respectively, reversed the increase in LV collagen in a dose- dependent manner. The mechanism by which Ac- SDKP reverses LV fibrosis does not appear to depend on ACE inhibition by Ac- SDKP, since we found that Ac- SDKP at various doses did not affect blood pressure responses to exogenous angiotensin I or bradykinin. However, Ac- SDKP reversed the increase in LV TGF-β and CTGF compared with rats with 2K- 1C plus vehicle ( P < 0.005). We concluded that in hypertension, Ac- SDKP reverses cardiac fibrosis, perhaps due in part to a decrease in TGF-beta and CTGF in the heart.