Bradykinin Protects Against Brain Microvascular Endothelial Cell Death Induced by Pathophysiological Stimuli
Bradykinin Protects Against Brain Microvascular Endothelial Cell Death Induced by Pathophysiological Stimuli
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DOI：
10.1002/jcp.21933
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发表时间：
2010-01-01
影响因子：
5.6
通讯作者：
Gobeil, Fernand, Jr.
中科院分区：
文献类型：
--
作者：
Bovenzi, Veronica;Savard, Martin;Gobeil, Fernand, Jr.
微循环的形态和功能完整性在许多心血管疾病（例如高血压、糖尿病、中风和败血症）中受到损害。血管紧张素转换酶抑制剂 (ACEi) 已知通过降低缓激肽 (BK) 的代谢来促进其生物活性，可能对预防这些疾病中发生的微血管结构稀疏产生积极影响。我们的研究旨在检验以下假设：BK 通过 B2 受体 (B2R) 保护暴露于坏死和凋亡细胞死亡诱导剂 H2O2 和 LPS 的微血管内皮的活力，与血流动力学无关。表达（RT-PCR 和放射性配体结合）和功能（使用 Furs-2AM 动员钙、p42/p44MAPK 和 Akt 磷酸化测定）实验揭示了猪脑微血管内皮细胞 (pCMVEC) 中存在功能性 B2R。体外结果表明，BK 预处理（MTT 和结晶紫测试、膜联蛋白-V 染色/FACS 分析）显着降低了 H2O2 和 LIPS 对 pCMVEC 的杀细胞作用，而 B2R 拮抗剂 HOE 140 可以抵消这种作用。BK 处理与细胞保护蛋白 COX-2、Bcl-2 和 (SOD)-S-Cu/Zn 的表达增强同时发生。对大鼠脑外植体的离体测定表明，BK 可以阻止（大约 40%）H2O2 诱导的微血管变性（凝集素-FITC 染色）。本研究提出了 BK 在微血管内皮保护中的新作用，这可能与 ACEi 的复杂作用机制有关，解释了它们在维持血管完整性方面的长期有益作用。 J.细胞。生理学。 222: 168-176, 2010。(C) 2009 Wiley-Liss, Inc.
The morphological and functional integrity of the microcirculation is compromised in many cardiovascular diseases such as hypertension, diabetes, stroke, and sepsis. Angiotensin converting enzyme inhibitors (ACEi), which are known to favor bradykinin (BK) bioactivity by reducing its metabolism, may have a positive impact on preventing the microvascular structural rarefaction that occurs in these diseases. Our study was designed to test the hypothesis that BK, via B2 receptors (B2R), protects the viability of the microvascular endothelium exposed to the necrotic and apoptotic cell death inducers H2O2 and LPS independently of hemodynamics. Expression (RT-PCR and radioligand binding) and functional (calcium mobilization with furs-2AM, and p42/p44MAPK and Akt phosphorylation assays) experiments revealed the presence of functional B2R in pig cerebral microvascular endothelial cells (pCMVEC). In vitro results showed that the cytocidal effects of H2O2 and LIPS on pCMVEC were significantly decreased by a BK pretreatment (MTT and crystal violet tests, annexin-V staining/FACS analysis), which was countered by the B2R antagonist HOE 140. BK treatment coincided with enhanced expression of the cytoprotective proteins COX-2, Bcl-2, and (SOD)-S-Cu/Zn. Ex vivo assays on rat brain explants showed that BK impeded (by similar to 40%) H2O2-induced microvascular degeneration (lectin-FITC staining). The present study proposes a novel role for BK in microvascular endothelial protection, which may be pertinent to the complex mechanism of action of ACEi explaining their long-term beneficial effects in maintaining vascular integrity. J. Cell. Physiol. 222: 168-176, 2010. (C) 2009 Wiley-Liss, Inc.