Mitochondrial requirement for endothelial responses to cyclic strain: implications for mechanotransduction

被引:124
作者
Ali, MH [1 ]
Pearlstein, DP [1 ]
Mathieu, CE [1 ]
Schumacker, PT [1 ]
机构
[1] Univ Chicago, Dept Med, Sect Pulm & Crit Care, Chicago, IL 60637 USA
关键词
reactive oxygen species; mitochondria; vascular cell adhesion molecule-1; superoxide; hypertension; atherosclerosis; cytoskeleton; cyclic stretch;
D O I
10.1152/ajplung.00389.2003
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Mechanical strain triggers a variety of cellular responses, but the underlying mechanotransduction process has not been established. Endothelial cells (EC) respond to mechanical strain by upregulating adhesion molecule expression through a signaling process involving reactive oxygen species (ROS), but the site of their generation is unknown. Mitochondria anchor to the cytoskeleton and could function as mechanotransducers by releasing ROS during cytoskeletal strain. In human umbilical vein EC ( HUVEC), ROS production increased 221 +/- 17% during 6 h of cyclic strain vs. unstrained controls. Mitochondrial inhibitors diphenylene iodonium or rotenone abrogated this response, whereas inhibitors of nitric oxide ( NO) synthase (L-nitroarginine), xanthine oxidase ( allopurinol), or NAD(P)H oxidase ( apocynin) had no effect. The antioxidants ebselen and diethyldithiocarbamate inhibited the increase in ROS, but the NO scavenger Hb had no effect. Thus strain induces ROS release from mitochondria. In other studies, HUVEC were rendered mitochondria deficient (rho(0) EC) to determine the requirement for electron transport in the response to strain. Strain-induced 2'7'-dichlorofluorescein fluorescence was attenuated by > 80% in rho(0) EC compared with HUVEC ( 43 +/- 7 vs. 221 +/- 17%). Treatment with cytochalasin D abrogated strain-induced ROS production, indicating a requirement for the actin cytoskeleton. Cyclic strain ( 6 h) increased VCAM-1 expression in wild-type but not rho(0) EC. Increases in NF-kappaB activation and VCAM-1 mRNA expression during strain were prevented by antioxidants. These findings demonstrate that mitochondria function as mechanotransducers in endothelium by increasing ROS signaling, which is required for strain-induced increase in VCAM-1 expression via NF-kappaB.
引用
收藏
页码:L486 / L496
页数:11
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