Aldosterone impairs bone marrow-derived progenitor cell formation
Aldosterone impairs bone marrow-derived progenitor cell formation
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DOI：
10.1161/01.hyp.0000235681.25685.cf
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发表时间：
2006-09-01
期刊：
影响因子：
8.3
通讯作者：
Fujita, Toshiro
中科院分区：
文献类型：
--
作者：
Marumo, Takeshi;Uchimura, Hideki;Fujita, Toshiro
最近已经提出醛固酮除了通过升高血压引起损伤之外，还通过直接作用于脉管系统引起血管损伤。骨髓来源的内皮祖细胞（EPCs）已被证明在内皮修复中发挥重要作用。此外，使用EPCs的基于细胞的治疗正在成为心肌和外周血管疾病的一种新的治疗策略。然而，在具有心血管疾病危险因素的患者中观察到EPCs的形成和功能受损。我们通过检测骨髓单个核细胞体外祖细胞形成来评估醛固酮对EPCs的可能影响。醛固酮（10 - 1000 nmol/L）以浓度依赖性方式减少祖细胞的形成。醛固酮的这一作用可通过与螺内酯联合治疗而减弱。醛固酮降低了血管内皮生长因子（VEGF）受体（VEGFR）2的mRNA水平，而对祖细胞中VEGF的产生或VEGF和肝细胞生长因子的mRNA水平没有任何影响。然而，基质源性生长因子1 mRNA的表达矛盾地增加。与VEGFR-2的下调一致，VEGF诱导的Akt磷酸化在醛固酮处理后的祖细胞中被消除。抗氧化剂N-乙酰半胱氨酸可减弱醛固酮的抑制作用。这些数据表明，醛固酮抑制骨髓来源的祖细胞的形成，至少部分，通过减弱VEGFR-2的表达和随后的Akt信号。因此，降低醛固酮水平、阻断盐皮质激素受体和/或与抗氧化剂共治疗可能增强内皮祖细胞的血管再生。
Aldosterone has been suggested recently to cause vascular injury by directly acting on the vasculature, in addition to causing injury by raising the blood pressure. Bone marrow-derived endothelial progenitor cells (EPCs) have been shown to exert an important role in the repair of the endothelium. In addition, cell-based therapy using EPCs is emerging as a novel therapeutic strategy for myocardial and peripheral vascular diseases. However, impaired formation and function of EPCs has been observed in patients with risk factors for cardiovascular diseases. We evaluated the possible effects of aldosterone on EPCs by examining the progenitor cell formation from bone marrow mononuclear cells ex vivo. Aldosterone (10 to 1000 nmol/L) reduced the formation of progenitor cells in a concentration-dependent manner. This effect of aldosterone was attenuated by cotreatment with spironolactone. Aldosterone reduced the mRNA levels of vascular endothelial growth factor (VEGF) receptor (VEGFR) 2 without having any effect on the production of VEGF or mRNA levels of VEGF and hepatocyte growth factor in the progenitor cells. However, the expression of stromal-derived growth factor 1 mRNA was paradoxically increased. Consistent with the downregulation of VEGFR-2, VEGF-induced phosphorylation of Akt was abolished in the progenitor cells after aldosterone treatment. N-acetylcysteine, an antioxidant, attenuated the inhibitory effects of aldosterone. These data indicate that aldosterone inhibits the formation of bone marrow-derived progenitor cells, at least partly, by attenuating VEGFR-2 expression and the subsequent Akt signaling. Reduction of aldosterone levels, blockade of mineralocorticoid receptor, and/or cotreatment with antioxidants may, therefore, enhance vascular regeneration by EPCs.