molecular mechanisms in the formation and rupture of cerebral aneurysm and impact of drug treatment

脑动脉瘤形成、破裂的分子机制及药物治疗的影响

• 批准号: 21390412
• 负责人: NAGAHIRO Shinji
• 金额: $ 11.15万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21390412/
• 关键词: 脳動脈瘤; タイトジャンクション蛋白; mineral corticoid receptor; phosphodiesterase; 血管内皮障害; angiotensin II; エストロゲン; 炎症; タイトジャンクショク蛋白

The pathogensis of cerebral aneursysm is multifactorial. To elucidate on how to generate, grow, and rupture, we establish a reproducible aneurysmal model in estrogen deficient female rats. Using this model, we first demonstrated that the reduction of tight junction protein induced by oxidative stress and inflammatory led to the degradation of endothelial gap, thereby facilitating the infiltration of macrophages into the aneurysmal wall. The increase in macrophage promotes inflammation, directed to vice cycle, resulting in the growth and rupture of cerebral aneurysm. To assess whether some drugs are possible to inhibit the formation and growth of cerebral aneurysms, we used an angiotensin typeI receptor a blockade,phosphodiesterase 4 inhibitor, 17・estradiol in hormonal replacement therapy and a mineralcorticoid receptor antagonist.These drugs were effective to prevent the formation of cerebral aneurysms and the mechanism underlying the effects by these drugs associated with anti-oxidative and anti-inflammatory. On the other hand, statins exerted diverse effects; beneficial and deleterious effects. Notably, a high dose satin and a lipophilic statin induced rupture. Furthermore, we found new evidence that the combination of estrogen deficiency and high salt intake is exclusively associated with the formation of cerebral aneurysm. In the further study, we will verify the relationship between high salt intake and cerebral aneurysms.

脑动脉瘤的发病机制是多因素的。为了阐明如何发生、生长和破裂，我们在雌激素缺乏的雌性大鼠上建立了一个可复制的动脉瘤模型。利用这一模型，我们首次证明了氧化应激和炎症导致紧密连接蛋白的减少导致内皮细胞间隙的降解，从而促进巨噬细胞向动脉瘤壁内的渗透。巨噬细胞的增多促进炎症，导向副循环，导致脑动脉瘤的生长和破裂。为了评价某些药物是否有可能抑制脑动脉瘤的形成和生长，我们使用了血管紧张素I型受体阻滞剂、磷酸二酯酶4抑制剂、激素替代疗法中的17·雌二醇和矿化皮质激素受体拮抗剂。这些药物有效地预防了脑动脉瘤的形成，并探讨了这些药物与抗氧化和抗炎相关的作用机制。另一方面，他汀类药物发挥着不同的作用，既有有益的，也有有害的。值得注意的是，高剂量的他汀类药物和亲脂性的他汀类药物会导致破裂。此外，我们发现新的证据表明，雌激素缺乏和高盐摄入量的组合仅与脑动脉瘤的形成有关。在进一步的研究中，我们将验证高盐摄入量与脑动脉瘤的关系。

项目成果

Statins Promote the Growth of Experimentally Induced Cerebral Aneurysms in Estrogen-Deficient Rats

• DOI: 10.1161/strokeaha.110.608034
• 发表时间: 2011-08-01
• 期刊: STROKE
• 影响因子: 8.3
• 作者: Tada, Yoshiteru;Kitazato, Keiko T.;Nagahiro, Shinji
• 通讯作者: Nagahiro, Shinji