Protective role of clusterin in preserving endothelial function in AL amyloidosis.
Protective role of clusterin in preserving endothelial function in AL amyloidosis.
复制标题
DOI：
10.1016/j.atherosclerosis.2012.08.028
复制
发表时间：
2012-11
期刊：
影响因子：
5.3
通讯作者：
Migrino, Raymond Q.
中科院分区：
文献类型：
--
作者：
Franco, Daniel A.;Truran, Seth;Burciu, Camelia;Gutterman, David D.;Maltagliati, Anthony;Weissig, Volkmar;Hari, Parameswaran;Migrino, Raymond Q.
轻链淀粉样变性（AL）中错误折叠的免疫球蛋白轻链蛋白（LC）对血管组织具有毒性。我们测试了伴侣蛋白聚集蛋白在LC暴露期间保留内皮功能和细胞存活的假设。将LC（20 μg/mL）给予人主动脉内皮细胞（EC）24小时，并测量丛生蛋白（clusterin）蛋白/基因表达和分泌。用/不用重组丛生蛋白（Clu，300 ng/mL）测量DNA片段化。在基线和LC±Clu 1小时后，检测脂肪小动脉（非AL受试者）对乙酰胆碱/罂粟碱的扩张反应。LC降低EC丛生蛋白的分泌、蛋白和基因表达，同时增加DNA片段化。Clu减弱了LC诱导的DNA断裂，并恢复了扩张器对乙酰胆碱的反应（logEC 50：对照−7.05±0.2，LC+Clu −6.53±0.4，LC −4.28±0.7，p<0.05 vs. control，LC+Clu）。LC诱导内皮细胞死亡和功能障碍，同时减少clusterin蛋白/基因的表达和分泌。外源性clusterin减轻LC毒性。这为AL淀粉样变性的发病机制和治疗提供了新的靶点。
Misfolded immunoglobulin light chain proteins (LC) in light chain amyloidosis (AL) are toxic to vascular tissues. We tested the hypothesis that chaperone protein clusterin preserves endothelial function and cell survival during LC exposure. LC (20 μg/mL) were given to human aortic endothelial cells (EC) for 24-hours and clusterin protein/gene expression and secretion were measured. DNA fragmentation was measured with/without recombinant clusterin (Clu, 300 ng/mL). Adipose arterioles (non-AL subjects) were tested for dilator responses to acetylcholine/papaverine at baseline and after 1-hour of LC±Clu. LC reduced EC clusterin secretion, protein and gene expression while increasing DNA fragmentation. Clu attenuated LC-induced DNA fragmentation and restored dilator response to acetylcholine (logEC50: control −7.05±0.2, LC+Clu −6.53±0.4, LC −4.28±0.7, p<0.05 vs. control, LC+Clu). LC induced endothelial cell death and dysfunction while reducing clusterin protein/gene expression and secretion. Exogenous clusterin attenuated LC toxicity. This represents a new pathobiologic mechanism and therapeutic target for AL amyloidosis.
登录
查看更多内容
影响因子：
--
作者：
Thambisetty, Madhav;Simmons, Andrew;Velayudhan, Latha;Hye, Abdul;Campbell, James;Zhang, Yi;Wahlund, Lars-Olof;Westman, Eric;Kinsey, Anna;Guntert, Andreas;Proitsi, Petroula;Powell, John;Causevic, Mirsada;Killick, Richard;Lunnon, Katie;Lynham, Steven;Broadstock, Martin;Choudhry, Fahd;Howlett, David R.;Williams, Robert J.;Sharp, Sally I.;Mitchelmore, Cathy;Tunnard, Catherine;Leung, Rufina;Foy, Catherine;O'Brien, Darragh;Breen, Gerome;Furney, Simon J.;Ward, Malcolm;Kloszewska, Iwona;Mecocci, Patrizia;Soininen, Hilkka;Tsolaki, Magda;Vellas, Bruno;Hodges, Angela;Murphy, Declan G. M.;Parkins, Sue;Richardson, Jill C.;Resnick, Susan M.;Ferrucci, Luigi;Wong, Dean F.;Zhou, Yun;Muehlboeck, Sebastian;Evans, Alan;Francis, Paul T.;Spenger, Christian;Lovestone, Simon
通讯作者：
Lovestone, Simon
DOI：
10.1016/j.echo.2009.09.012
发表时间：
2009-12
影响因子：
6.5
作者：
Migrino, Raymond Q.;Mareedu, Ravi K.;Eastwood, Daniel;Bowers, Mark;Harmann, Leanne;Hari, Parameswaran
通讯作者：
Hari, Parameswaran
影响因子：
6
作者：
Greene, Michael J.;Sam, Flora;Connor, Lawreen H.
通讯作者：
Connor, Lawreen H.
DOI：
10.1152/ajpheart.00503.2011
发表时间：
2011-12-01
影响因子：
4.8
作者：
Migrino, Raymond Q.;Truran, Seth;Hari, Parameswaran
通讯作者：
Hari, Parameswaran
影响因子：
11.2
作者：
Berghoff, M;Kathpal, M;Freeman, R
通讯作者：
Freeman, R