Pharmacologic inhibition by spironolactone attenuates experimental abdominal aortic aneurysms.
Pharmacologic inhibition by spironolactone attenuates experimental abdominal aortic aneurysms.
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DOI：
10.3389/fcvm.2023.1101389
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发表时间：
2023
影响因子：
3.6
通讯作者：
Sharma AK
中科院分区：
文献类型：
--
作者：
Ladd Z;Su G;Hartman J;Lu G;Hensley S;Upchurch GR Jr;Sharma AK
腹主动脉瘤 (AAA) 的特点是血管炎症和重塑，可导致主动脉破裂，导致严重死亡。内皮细胞 (EC) 上的 Pannexin-1 通道可以调节 ATP 分泌，从而调节 AAA 形成的发病机制。我们的假设集中于螺内酯抑制 EC 介导的 ATP 释放以减轻 AAA 形成的潜力。局部弹性蛋白酶 AAA 模型最初用于 C57BL/6（野生型；WT）雄性小鼠。给小鼠施用载体对照（盐水）或螺内酯，并在第 14 天进行分析。在第二个慢性 AAA 模型中，从第 14 天开始，对小鼠进行弹性蛋白酶和 β-氨基丙腈 (BAPN) 治疗，同时对预先形成的动脉瘤施用或不施用螺内酯，并在第 28 天进行分析。通过视频测微法评估主动脉直径，并分析主动脉组织的细胞因子表达和组织学。在第 14 天或-28 天评估主动脉组织中的 ATP 测量和基质金属蛋白酶 (MMP2) 活性。进行体外研究以评估主动脉内皮细胞与巨噬细胞或平滑肌细胞之间的串扰。在弹性蛋白酶 AAA 模型中，第 14 天，与弹性蛋白酶处理的对照组相比，螺内酯治疗显示主动脉直径显着减小。与盐水处理的对照组相比，螺内酯处理的小鼠观察到平滑肌 α-肌动蛋白表达显着增加，弹性纤维破坏和免疫细胞（巨噬细胞和中性粒细胞）浸润减少。与对照组相比，螺内酯治疗还显着减轻了主动脉组织中促炎细胞因子的表达、MMP2 活性和 ATP 含量。此外，在慢性 AAA 模型中，与对照组相比，螺内酯治疗预先形成的动脉瘤可显着减轻血管炎症和重塑，从而减缓 AAA 的进展。从机制上讲，体外数据表明螺内酯治疗可减弱内皮细胞的细胞外 ATP 释放，从而减轻巨噬细胞激活（IL-1β 和 HMGB1 表达）和平滑肌细胞依赖性血管重塑（MMP2 活性）。这些结果表明，螺内酯可以减轻主动脉炎症和重塑，从而减弱 AAA 的形成，并通过抑制 EC 依赖性 ATP 释放来减少预先形成的动脉瘤的生长。因此，本研究暗示螺内酯在 AAA 治疗中的治疗应用。
Abdominal aortic aneurysms (AAA) are characterized by vascular inflammation and remodeling that can lead to aortic rupture resulting in significant mortality. Pannexin-1 channels on endothelial cells (ECs) can modulate ATP secretion to regulate the pathogenesis of AAA formation. Our hypothesis focused on potential of spironolactone to inhibit EC-mediated ATP release for the mitigation of AAA formation. A topical elastase AAA model was used initially in C57BL/6 (wild-type; WT) male mice. Mice were administered either a vehicle control (saline) or spironolactone and analyzed on day 14. In a second chronic AAA model, mice were subjected to elastase and β-aminopropionitrile (BAPN) treatment with/without administration of spironolactone to pre-formed aneurysms starting on day 14 and analyzed on day 28. Aortic diameter was evaluated by video micrometry and aortic tissue was analyzed for cytokine expression and histology. ATP measurement and matrix metalloproteinase (MMP2) activity was evaluated in aortic tissue on days 14 or -28. In vitro studies were performed to evaluate the crosstalk between aortic ECs with macrophages or smooth muscle cells. In the elastase AAA model, spironolactone treatment displayed a significant decrease in aortic diameter compared to elastase-treated controls on day 14. A significant increase in smooth muscle α-actin expression as well as decrease in elastic fiber disruption and immune cell (macrophages and neutrophils) infiltration was observed in mice treated with spironolactone compared to saline-treated controls. Spironolactone treatment also significantly mitigated pro-inflammatory cytokine expression, MMP2 activity and ATP content in aortic tissue compared to controls. Moreover, in the chronic AAA model, spironolactone treatment of pre-formed aneurysms significantly attenuated vascular inflammation and remodeling to attenuate the progression of AAAs compared to controls. Mechanistically, in vitro data demonstrated that spironolactone treatment attenuates extracellular ATP release from endothelial cells to mitigate macrophage activation (IL-1β and HMGB1 expression) and smooth muscle cell-dependent vascular remodeling (MMP2 activity). These results demonstrate that spironolactone can mitigate aortic inflammation and remodeling to attenuate AAA formation as well as decrease growth of pre-formed aneurysms via inhibition of EC-dependent ATP release. Therefore, this study implicates a therapeutic application of spironolactone in the treatment of AAAs.
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影响因子：
16.6
作者：
Lohman AW;Leskov IL;Butcher JT;Johnstone SR;Stokes TA;Begandt D;DeLalio LJ;Best AK;Penuela S;Leitinger N;Ravichandran KS;Stokes KY;Isakson BE
通讯作者：
Isakson BE
DOI：
10.1161/atvbaha.112.300432
发表时间：
2013-02
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Johnston WF;Salmon M;Su G;Lu G;Stone ML;Zhao Y;Owens GK;Upchurch GR Jr;Ailawadi G
通讯作者：
Ailawadi G
影响因子：
20.1
作者：
Good, Miranda E.;Chiu, Yu-Hsin;Ravichandran, Kodi S.
通讯作者：
Ravichandran, Kodi S.
DOI：
10.1124/jpet.114.220210
发表时间：
2015-04-01
影响因子：
3.5
作者：
Kaneko, Yosuke;Tachikawa, Masanori;Terasaki, Tetsuya
通讯作者：
Terasaki, Tetsuya
影响因子：
4.3
作者：
ANIDJAR, S;DOBRIN, PB;CHEJFEC, G
通讯作者：
CHEJFEC, G