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.

Download full-text


Available from: Guohao Dai, Jul 29, 2015
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The cardiovascular system is susceptible to a group of diseases that are responsible for a larger proportion of morbidity and mortality than any other disease. Many cardiovascular diseases are associated with a failure of defenses against oxidative stress-induced cellular damage and/or death, leading to organ dysfunction. The pleiotropic transcription factor, nuclear factor-erythroid (NF-E) 2-related factor 2 (Nrf2), regulates the expression of antioxidant enzymes and proteins through the antioxidant response element. Nrf2 is an important component in antioxidant defenses in cardiovascular diseases such as atherosclerosis, hypertension, and heart failure. Nrf2 is also involved in protection against oxidant stress during the processes of ischemia-reperfusion injury and aging. However, evidence suggests that Nrf2 activity does not always lead to a positive outcome and may accelerate the pathogenesis of some cardiovascular diseases (e.g., atherosclerosis). The precise conditions under which Nrf2 acts to attenuate or stimulate cardiovascular disease processes are unclear. Further studies on the cellular environments related to cardiovascular diseases that influence Nrf2 pathways are required before Nrf2 can be considered a therapeutic target for the treatment of cardiovascular diseases.
    Oxidative medicine and cellular longevity 04/2013; DOI:10.1155/2013/104308 · 3.36 Impact Factor
  • Source
    • "However in this complex and specialized architecture, the endothelium layer certainly rep‐ resents the first sensor of hemodynamic stress [6] and the favorite target for atherogenic fac‐ tors, like circulating inflammatory molecules, macrophages, lipoproteins (LDLs) and many drugs [7]. "
    Current Trends in Atherogenesis, Edited by Prof.Rezzani R, 02/2013: chapter 2: pages 27-54; InTech., ISBN: 978-953-51-1011-8
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress has been implicated as a causative factor of atherosclerosis. Defense systems against oxidative stress are maintained by radical scavenging antioxidants and/or by regulating the expression of antioxidant genes by activating oxidative stress-sensitive transcription factor: nuclear factor (erythroid-derived 2)-like 2 (Nrf2). We investigated the anti-atherogenic effects of three synthesized compounds (shogaol A: radical scavenging antioxidant activity; shogaol N: Nrf2-activating activity; shogaol N + A: both activities) and curcumin (both activities) in apolipoprotein E (apoE)-deficient mice. We expected compounds with both activities to have additive or synergistic anti-atherogenic effects; however, atherosclerosis was exacerbated significantly by curcumin and slightly by shogaol N + A. Shogaol A, shogaol N, and shogaol N + A showed no significant effect on atherosclerosis development. Immunohistochemical analysis of the aorta revealed that expression of CD36, an Nrf2-regulated gene, was strongly induced by treatment with curcumin. The total antioxidant capacity of plasma collected from mice administered the three compounds was evaluated using a hydrophilic probe, pyranine. Shogaol N or shogaol N + A significantly enhanced the antioxidant capacity of plasma, whereas shogaol A and curcumin did not show this activity. The concentrations of the three shogaol derivatives in plasma were similar (approximately 100 nM), while that of curcumin was much lower. These results suggest that plasma antioxidant capacity is maintained at high levels via Nrf2 activation and that CD36 expression enhances atherosclerosis development.
    Atherosclerosis 08/2012; 225(1):83-90. DOI:10.1016/j.atherosclerosis.2012.08.023 · 3.97 Impact Factor
Show more