Increased aortic calpain-1 activity mediates age-associated angiotensin II signaling of vascular smooth muscle cells.
Increased aortic calpain-1 activity mediates age-associated angiotensin II signaling of vascular smooth muscle cells.
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主动脉Calpain-1活性增加可介导与年龄相关的血管紧张素II信号的血管平滑肌细胞信号传导。
DOI：
10.1371/journal.pone.0002231
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发表时间：
2008-05-21
期刊：
影响因子：
3.7
通讯作者：
Lakatta, Edward G.
中科院分区：
文献类型：
--
作者：
Jiang, Liqun;Wang, Mingyi;Zhang, Jing;Monticone, Robert E.;Telljohann, Richard;Spinetti, Gaia;Pintus, Gianfranco;Lakatta, Edward G.
血管紧张素 II (Ang II) 信号传导，包括 II 型基质金属蛋白酶 (MMP2) 激活，与年龄相关的血管平滑肌细胞 (VSMC) 迁移能力的增加以及动脉老化的其他促炎特征有关。 Calpain-1 激活是成纤维细胞中 MMP2 表达所必需的，并且在心肌细胞中由 Ang II 诱导。然而，calpain-1 与其底物结合在控制动脉壁内与年龄相关的促炎症状态方面的影响仍不清楚。目前的研究结果表明，与年轻大鼠（8 个月）相比，老年（30 个月）大鼠主动脉或早期主动脉 VSMC 中 calpain-1 的转录、翻译和活性显着上调。动脉壁的双重免疫标记表明，calpain-1 和 Ang II 的共定位在老化的动脉壁内增加。为了进一步探讨 calpain-1 与 Ang II 的关系，我们将 Ang II 长期注入年轻大鼠体内，并用 Ang II 处理培养的主动脉环或 VSMC。我们还构建了含有 calpain-1 (CANP1) 或其内源性抑制剂 calpastatin (CAST) 的腺病毒，并将其感染到 VSMC 中。 Ang II 在体内和离体主动脉壁中诱导 calpain-1 表达，在体外诱导 VSMC 表达。 Ang II 介导的、与年龄相关的 MMP2 活性增加和 VSMC 中的迁移均被钙蛋白酶抑制剂 1 或 CAST 阻断。年轻 VSMC 中 calpain-1 的过度表达会导致完整波形蛋白的裂解，并增加迁移能力，类似于老年 VSMC，这种能力被 MMP 抑制剂 GM6001 阻断。 Calpain-1 激活是年龄相关动脉 Ang II/MMP2 信号级联中的关键分子事件，与细胞骨架蛋白重组和 VSMC 迁移相关。因此，靶向 calpain-1 有可能延迟或逆转与年龄相关的疾病（即动脉粥样硬化）的动脉重塑。
Angiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMC), and to other proinflammatory features of arterial aging. Calpain-1 activation is required for MMP2 expression in fibroblasts and is induced in cardiomyocytes by Ang II. The consequences of engagement of calpain-1 with its substrates, however, in governing the age-associated proinflammatory status within the arterial wall, remains unknown. The present findings demonstrate that transcription, translation, and activity of calpain-1 are significantly up-regulated in rat aortae or early-passage aortic VSMC from old (30-mo) rats compared to young (8-mo). Dual immunolabeling of the arterial wall indicates that colocalization of calpain-1 and Ang II increases within the aged arterial wall. To further explore the relationship of calpain-1 to Ang II, we chronically infused Ang II into young rats, and treated cultured aortic rings or VSMC with Ang II. We also constructed adenoviruses harboring calpain-1 (CANP1) or its endogenous inhibitor calpastatin (CAST) and infected these into VSMC. Ang II induces calpain-1 expression in the aortic walls in vivo and ex vivo and VSMC in vitro. The Ang II mediated, age-associated increased MMP2 activity and migration in VSMC are both blocked by calpain inhibitor 1 or CAST. Over-expression of calpain-1 in young VSMC results in cleavage of intact vimentin, and an increased migratory capacity mimicking that of old VSMC, which is blocked by the MMP inhibitor, GM6001. Calpain-1 activation is a pivotal molecular event in the age-associated arterial Ang II/MMP2 signaling cascade that is linked to cytoskeleton protein restructuring, and VSMC migration. Therefore, targeting calpain-1 has the potential to delay or reverse the arterial remodeling that underlies age-associated diseases i.e. atherosclerosis.
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影响因子：
4
作者：
Bialkowska, K;Saido, TC;Fox, JEB
通讯作者：
Fox, JEB
DOI：
10.1196/annals.1372.011
发表时间：
2006-01-01
期刊：
DIABETES MELLITUS AND ITS COMPLICATIONS
影响因子：
--
作者：
Harris, Frederick;Biswas, Suman;Phoenix, David A.
通讯作者：
Phoenix, David A.
影响因子：
3.5
作者：
HATA, A;OHNO, S;SUZUKI, K
通讯作者：
SUZUKI, K
影响因子：
4.1
作者：
ISHII, H;SUZUKI, Y;KAZAMA, M
通讯作者：
KAZAMA, M
DOI：
10.1161/01.atv.0000236428.91125.e6
发表时间：
2006-09-01
影响因子：
8.7
作者：
Bennett, Brian J.;Scatena, Marta;Rosenfeld, Michael E.
通讯作者：
Rosenfeld, Michael E.