Inhibition of angiotensin I-converting enzyme induces radioprotection by preserving murine hematopoietic short-term reconstituting cells
Inhibition of angiotensin I-converting enzyme induces radioprotection by preserving murine hematopoietic short-term reconstituting cells
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DOI：
10.1182/blood-2003-11-3828
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发表时间：
2004-08-15
期刊：
影响因子：
20.3
通讯作者：
Vainchenker, W
中科院分区：
文献类型：
--
作者：
Charrier, S;Michaud, A;Vainchenker, W
血管紧张素I转化酶（ACE）抑制剂可通过多种机制影响造血，包括抑制血管紧张素II形成和增加AcSDKP（乙酰基-N-Ser-Asp-Lys-Pro）（ACE底物和造血负调节剂）的血浆浓度。我们测试了ACE抑制是否可以降低致死或亚致死照射方案的造血毒性。在所有情况下，短期治疗与ACE抑制剂培哚普利防止辐射诱导的死亡。ACE抑制加速造血恢复，并导致血小板和红细胞计数显着增加。培哚普利预处理可增加照射后第7 - 28天骨髓细胞构成和造血祖细胞（粒细胞巨噬细胞集落形成单位[CFU-GM]、红系爆发形成单位[BFU-E]和巨核细胞集落形成单位[CFU-MK]）数量。培哚普利还增加了从辐射中恢复的动物中具有至少短期重建活性的造血干细胞的数量。为了确定所涉及的作用机制，我们评估了AcSDKP血浆浓度增加和血管紧张素II 1型（AT 1）受体拮抗剂（替米沙坦）对辐射防护的影响。我们发现，AT 1受体拮抗剂介导类似的辐射保护的ACE抑制剂。提示ACE抑制剂和AT_1受体拮抗剂可减轻辐射的造血毒性。(C)2004年，美国血液学会。
Angiotensin I-converting enzyme (ACE) inhibitors can affect hematopoiesis by several mechanisms including inhibition of angiotensin II formation and increasing plasma concentrations of AcSDKP (acetyl-N-Ser-Asp-Lys-Pro), an ACE substrate and a negative regulator of hematopoiesis. We tested whether ACE inhibition could decrease the hematopoietic toxicity of lethal or sublethal irradiation protocols. In all cases, short treatment with the ACE inhibitor perindopril protected against irradiation-induced death. ACE inhibition accelerated hematopoietic recovery and led to a significant increase in platelet and red cell counts. Pretreatment with perindopril increased bone marrow cellularity and the number of hematopoietic progenitors (granulocyte macrophage colony-forming unit [CFU-GM], erythroid burst-forming unit [BFU-E], and megakaryocyte colony-forming unit [CFU-MK]) from day 7 to 28 after irradiation. Perindopril also increased the number of hematopoietic stem cells with at least a short-term reconstitutive activity in animals that recovered from irradiation. To determine the mechanism of action involved, we evaluated the effects of increasing AcSDKP plasma concentrations and of an angiotensin II type 1 (AT1) receptor antagonist (telmisartan) on radioprotection. We found that the AT1-receptor antagonism mediated similar radioprotection as the ACE inhibitor. These results suggest that ACE inhibitors and AT1-receptor antagonists could be used to decrease the hematopoietic toxicity of irradiation. (C) 2004 by The American Society of Hematology.