Biomechanical forces in atherosclerosis-resistant vascular regions regulate endothelial redox balance via phosphoinositol 3-kinase/Akt-dependent activation of Nrf2.
Local patterns of biomechanical forces experienced by endothelial cells (ECs) in different vascular geometries appear to play an essential role in regulating EC function and determining the regional susceptibility to atherosclerosis, even in the face of systemic risk factors. To study how biomechanical forces regulate EC redox homeostasis, an important pathogenic factor in atherogenesis, we have cultured human ECs under 2 prototypic arterial shear stress waveforms, "atheroprone" and "atheroprotective," which were derived from 2 distinct vascular regions in vivo that are typically "susceptible" or "resistant" to atherosclerosis. We demonstrate that atheroprotective flow decreases EC intracellular redox level and protects ECs against oxidative stress-induced injury. To identify the molecular mechanisms that control this cellular response, we examined several major oxidative/antioxidative pathways and found that atheroprotective flow upregulated certain antioxidant genes and strongly activated the transcription factor Nrf2. Using a strategy of small interfering RNA inhibition of Nrf2 expression combined with genome-wide transcriptional profiling, we determined the downstream targets of Nrf2 activation and identified Nrf2 as a critical determinant for the changes in endothelial redox balance exerted by atheroprotective flow. In addition, we showed that atheroprotective flow activates Nrf2 via the phosphoinositol 3-kinase/Akt pathway, and this activation occurs differentially in atherosclerosis-resistant and atherosclerosis-susceptible regions of the mouse aorta. Taken together, our data demonstrate that hemodynamic forces present in atherosclerosis-resistant and -susceptible regions of the vasculature differentially regulate EC redox state and antioxidant potential. These alterations in redox homeostasis are primarily the result of the phosphoinositol 3-kinase/Akt-dependent activation of Nrf2 and its downstream transcriptional targets.
Dai
Guohao
G
Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass 02115-6110, USA.
Vaughn
Saran
S
Zhang
Yuzhi
Y
Wang
Eric T
ET
Garcia-Cardena
Guillermo
G
Gimbrone
Michael A
MA
D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000502:physiology; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis* / Q000235:genetics; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000235:genetics; D013314:Stress, Mechanical; D014158:Transcription, Genetic
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt