TY - JOUR
T1 - A novel mechanism of γ/σ T-lymphocyte and endothelial activation by shear stress
T2 - The role of ecto-ATP synthase β chain
AU - Fu, Yi
AU - Hou, Yingjian
AU - Fu, Chenglai
AU - Gu, Mingxia
AU - Li, Chenghong
AU - Kong, Wei
AU - Wang, Xian
AU - Shyy, John Y.J.
AU - Zhu, Yi
PY - 2011/2/18
Y1 - 2011/2/18
N2 - RATIONALE: Endothelial cells (ECs) have distinct mechanotransduction mechanisms responding to laminar versus disturbed flow patterns. Endothelial dysfunction, affected by imposed flow, is one of the earliest events leading to atherogenesis. The involvement of γ/σ T lymphocytes in endothelial dysfunction under flow is largely unknown. OBJECTIVE: To investigate whether shear stress regulates membrane translocation of ATP synthase β chain (ATPSβ) in ECs, leading to the increased γ/σ T-lymphocyte adhesion and the related functions. METHOD AND RESULTS: We applied different flow patterns to cultured ECs. Laminar flow decreased the level of membrane-bound ATPSβ (ecto-ATPSβ) and depleted membrane cholesterol, whereas oscillatory flow increased the level of ecto-ATPSβ and membrane cholesterol. Incubating ECs with cholesterol or depleting cellular cholesterol with β-cyclodextrin mimicked the effect of oscillatory or laminar flow, respectively. Knockdown caveolin-1 by small interfering RNA prevented ATPSβ translocation in response to laminar flow. Importantly, oscillatory flow or cholesterol treatment elevated the number of γ/σ T cells binding to ECs, which was blocked by anti-ATPSβ antibody. Furthermore, the incubation of γ/σ T cells with ECs increased tumor necrosis fact α and interferon-γ secretion from T cells and vascular cell adhesion molecule-1 expression in ECs. In vivo, γ/σ T-cell adhesion and ATPSβ membrane translocation was elevated in the aortic inner curvature and disturbed flow areas in partially ligated carotid arteries of ApoE-/- mice fed a high-fat diet. CONCLUSIONS: This study provides evidence that disturbed flow and hypercholesterolemia synergistically promote γ/σ T-lymphocyte activation by the membrane translocation of ATPSβ in ECs and in vivo in mice, which is a novel mechanism of endothelial activation.
AB - RATIONALE: Endothelial cells (ECs) have distinct mechanotransduction mechanisms responding to laminar versus disturbed flow patterns. Endothelial dysfunction, affected by imposed flow, is one of the earliest events leading to atherogenesis. The involvement of γ/σ T lymphocytes in endothelial dysfunction under flow is largely unknown. OBJECTIVE: To investigate whether shear stress regulates membrane translocation of ATP synthase β chain (ATPSβ) in ECs, leading to the increased γ/σ T-lymphocyte adhesion and the related functions. METHOD AND RESULTS: We applied different flow patterns to cultured ECs. Laminar flow decreased the level of membrane-bound ATPSβ (ecto-ATPSβ) and depleted membrane cholesterol, whereas oscillatory flow increased the level of ecto-ATPSβ and membrane cholesterol. Incubating ECs with cholesterol or depleting cellular cholesterol with β-cyclodextrin mimicked the effect of oscillatory or laminar flow, respectively. Knockdown caveolin-1 by small interfering RNA prevented ATPSβ translocation in response to laminar flow. Importantly, oscillatory flow or cholesterol treatment elevated the number of γ/σ T cells binding to ECs, which was blocked by anti-ATPSβ antibody. Furthermore, the incubation of γ/σ T cells with ECs increased tumor necrosis fact α and interferon-γ secretion from T cells and vascular cell adhesion molecule-1 expression in ECs. In vivo, γ/σ T-cell adhesion and ATPSβ membrane translocation was elevated in the aortic inner curvature and disturbed flow areas in partially ligated carotid arteries of ApoE-/- mice fed a high-fat diet. CONCLUSIONS: This study provides evidence that disturbed flow and hypercholesterolemia synergistically promote γ/σ T-lymphocyte activation by the membrane translocation of ATPSβ in ECs and in vivo in mice, which is a novel mechanism of endothelial activation.
KW - ATP synthase
KW - T lymphocyte
KW - blood flow
KW - endothelial dysfunction
KW - mechanotransduction
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U2 - 10.1161/CIRCRESAHA.110.230151
DO - 10.1161/CIRCRESAHA.110.230151
M3 - Article
C2 - 21193741
AN - SCOPUS:79952071002
SN - 0009-7330
VL - 108
SP - 410
EP - 417
JO - Circulation research
JF - Circulation research
IS - 4
ER -