Article

Biomechanical forces in atherosclerosis-resistant vascular regions regulate endothelial redox balance via phosphoinositol 3-kinase/Akt-dependent activation of Nrf2

Harvard University, Cambridge, Massachusetts, United States
Circulation Research (Impact Factor: 11.09). 10/2007; 101(7):723-33. DOI: 10.1161/CIRCRESAHA.107.152942
Source: PubMed

ABSTRACT 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.

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    • "It is becoming increasingly apparent that Nrf2 is important to vascular integrity and long-term endothelial function, for example, sustained release of NO and protection from apoptosis [23] [24] [25] [26] [27] [28] [29]. Conversely, specific changes in vascular physiology that are related to Nrf2 can lead to increased susceptibility to atheroma development, such as increases in oxidative stress leading to oxidation of LDLs, reduced NO production, and increased levels of superoxide [20]. "
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    • "Most atherosclerosis-prone regions are exposed to nonunidirectional , disturbed, or oscillatory flow; in contrast, atherosclerosis-resistant regions are exposed to unidirectional laminar flow [13] [14]. Nrf2 is activated at atherosclerosis-resistant regions exposed to unidirectional and laminar flow, whereas Nrf2 is diffuse in atherosclerosis-prone regions exposed to disturbed flow [15]. On the other hand, the formation of atherosclerotic lesions was attenuated in apoE/Nrf2 double-deficient mice compared to in apoE-deficient mice. "
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