Calpain-1 regulation of matrix metalloproteinase 2 activity in vascular smooth muscle cells facilitates age-associated aortic wall calcification and fibrosis.
Calpain-1 regulation of matrix metalloproteinase 2 activity in vascular smooth muscle cells facilitates age-associated aortic wall calcification and fibrosis.
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DOI：
10.1161/hypertensionaha.112.196840
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Lakatta EG
中科院分区：
文献类型：
--
作者：
Jiang L;Zhang J;Monticone RE;Telljohann R;Wu J;Wang M;Lakatta EG
与年龄相关的中央动脉壁硬度与细胞外基质（ECM）重塑有关，包括纤维化和血管钙化。血管紧张素 II 诱导动脉壁中 2 型基质金属蛋白酶 (MMP2) 和 calpain-1 的表达和活性。但 calpain-1 在 MMP2 激活和 ECM 重塑中的作用仍不清楚。双重组织免疫标记表明 calpain-1 和 MMP2 在老年大鼠血管平滑肌细胞内共定位。 calpain-1 的过度表达在一定程度上通过增加膜型 1 MMP 与金属蛋白酶 2 组织抑制剂的比例来诱导 MMP2 转录本、蛋白质水平和活性。 calpain-1 过度表达诱导的 MMP2 激活的这些作用与胶原蛋白 I 和 III 的产生增加以及血管钙化有关。此外，在体外培养的血管平滑肌细胞和离体颈动脉环中，calpain-1的过度表达还会诱导转化生长因子-β1/Smad信号传导、弹性蛋白降解、碱性磷酸酶激活和总钙含量，但会降低钙化抑制剂、骨桥蛋白和骨连接蛋白的表达。此外，人主动脉内膜内的 calpain-1 和胶原蛋白 II 都随着年龄的增长而增加。有趣的是，在老年人的主动脉壁中，与大体正常区域相比，calpain-1 和胶原蛋白 II 在动脉硬化斑块区域中高度表达。 calpain-1 和 MMP2 两种蛋白酶的相互作用会导致活性 MMP2 的分泌，从而通过增强胶原蛋白生成和促进血管钙化来调节 ECM 重塑。这些结果表明 calpain-1 是一种新的候选分子，可以延缓与年龄相关的 ECM 重塑及其伴随的高血压和动脉粥样硬化风险。
Age-associated central arterial wall stiffness is linked to extracellular matrix (ECM) remodeling, including fibrosis and vascular calcification. Angiotensin II induces both matrix metalloproteinase type 2 (MMP2) and calpain-1 expression and activity in the arterial wall. But the role of calpain-1 in MMP2 activation and ECM remodeling remains unknown. Dual histo-immunolabeling demonstrates co-localization of calpain-1 and MMP2 within old rat vascular smooth muscle cells. Over-expression of calpain-1 induces MMP2 transcripts, protein levels and activity, in part, by increasing the ratio of membrane-type 1 MMPs to tissue inhibitor of metalloproteinases 2. These effects of calpain-1 over-expression-induced MMP2 activation are linked to increased collagen I and III production and vascular calcification. In addition, over-expression of calpain-1 also induces transforming growth factor-β1/Smad signaling, elastin degradation, alkaline phosphatase activation and total calcium content, but reduces the expression of calcification inhibitors, osteopontin and osteonectin, in cultured vascular smooth muscle cells in vitro and in carotid artery rings ex vivo. Furthermore, both calpain-1 and collagen II increase with aging within human aortic intima. Interestingly, in aged human aortic wall, both calpain-1 and collagen II are highly expressed in arteriosclerotic plaque areas compared to grossly normal areas. Cross-talk of two proteases, calpain-1 and MMP2, leads to secretion of active MMP2, which modulates ECM remodeling via enhancing collagen production and facilitating vascular calcification. These results establish calpain-1 as a novel molecular candidate to retard age-associated ECM remodeling and its attendant risk for hypertension and atherosclerosis.