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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"In addition, miR-221 targets PI3KR1 that is involved in the regulation of PI3K/Akt-mediated signaling that was shown to stimulate the atheroprotective transcription factor Nrf2 (nuclear factor (erythroid-derived 2)-like 2) . Notably, expression of Nrf2 in ECs is induced by mechanical forces (e.g., by shear stress)  and contributes to formation of the endothelial regional atherosclerosis-resistant phenotype in vessels  . In ECs, Nrf2 drives expression of several antioxidant genes and downregulates several inflammatory mediators such as monocyte chemoattractant protein(MCP- ) 1 and vascular cell adhesion molecule-1 (VCAM- 1) therefore enhancing antioxidant and anti-inflammatory properties of the arterial epithelium . "
[Show abstract][Hide abstract]ABSTRACT: A cluster of miR-221/222 is a key player in vascular biology through exhibiting its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). These miRNAs contribute to vascular remodeling, an adaptive process involving phenotypic and behavioral changes in vascular cells in response to vascular injury. In proliferative vascular diseases such as atherosclerosis, pathological vascular remodeling plays a prominent role. The miR-221/222 cluster controls development and differentiation of ECs but inhibits their proangiogenic activation, proliferation, and migration. miR-221/222 are primarily implicated in maintaining endothelial integrity and supporting quiescent EC phenotype. Vascular expression of miR-221/222 is upregulated in initial atherogenic stages causing inhibition of angiogenic recruitment of ECs and increasing endothelial dysfunction and EC apoptosis. In contrast, these miRNAs stimulate VSMCs and switching from the VSMC "contractile" phenotype to the "synthetic" phenotype associated with induction of proliferation and motility. In atherosclerotic vessels, miR-221/222 drive neointima formation. Both miRNAs contribute to atherogenic calcification of VSMCs. In advanced plaques, chronic inflammation downregulates miR-221/222 expression in ECs that in turn could activate intralesion neoangiogenesis. In addition, both miRNAs could contribute to cardiovascular pathology through their effects on fat and glucose metabolism in nonvascular tissues such as adipose tissue, liver, and skeletal muscles.
"Atheroma lesions tend to develop at vascular branch points where endothelial cells are exposed to oscillatory shear stress but not to steady laminar shear stress. In agreement with this observation, Nrf2 nuclear translocation is observed in athero-resistant regions of aorta  . Taken together, these findings show that endothelial Nrf2 functions as an anti-atherogenic factor through induction of anti-oxidative genes and suppression of inflammatory genes in response to various signals, including laminar shear stress. "
"As an antioxidative transcription factor, Nrf2 is considered important in atherosclerosis resistance (Howden 2013). In cultured human ECs under different shear stress, it has been demonstrated that atheroprotective flow strongly activates Nrf2 in a PI3K/Akt-dependent manner, and Nrf2 is the determining factor for the alterations in redox homeostasis under hemodymatic forces (Hosoya et al. 2005, Dai et al. 2007). In mice models, increased Nrf2 expression has been shown to indirectly protect macrophages from oxLDL-mediated injury via phase II antioxidant enzyme activity, whereas an absence of Nrf2 increased foam cell formation and atherosclerosis progression (Zhu et al. 2008). "
[Show abstract][Hide abstract]ABSTRACT: Endothelial dysfunction is an important risk factor for cardiovascular disease and represents the initial step in the pathogenesis of atherosclerosis. Failure to protect against oxidative stress induced cellular damage accounts for endothelial dysfunction in the majority of pathophysiological conditions. Numerous antioxidant pathways are involved in cellular redox homeostasis, among which the Nrf2/Keap1-ARE signaling pathway is perhaps the most prominent. Nuclear factor E2-related factor 2 (Nrf2), a transcription factor with a high sensitivity to oxidative stress, binds to antioxidant response elements (AREs) in the nucleus and promotes the transcription of a wide variety of antioxidant genes. Nrf2 is located in the cytoskeleton, adjacent to Kelch-like ECH associated protein 1 (Keap1). Keap1 acts as an adapter for Cul3/Rbx1-mediated ubiquitination and degradation of Nrf2, which decreases the activity of Nrf2 under physiological conditions. Oxidative stress causes Nrf2 to dissociate from Keap1 and subsequently translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes. Experimental evidence has established that Nrf2-driven free radical detoxification pathways are important endogenous homeostatic mechanisms associated with vasoprotection in the setting of aging, atherosclerosis, hypertension, ischemia and cardiovascular diseases. The aim of this review is to briefly summarize the mechanisms that regulate the Nrf2/Keap1-ARE signaling pathway and the latest advances in understanding how Nrf2 protects against oxidative stress-induced endothelial injuries. Further studies regarding the precise mechanisms by which Nrf2-regulated endothelial protection occurs are necessary to determine whether Nrf2 may serve as a therapeutic target in the treatment of cardiovascular diseases.
Preview · Article · Apr 2015 · Journal of Endocrinology