We previously reported that laminar flow activates peroxisome proliferator-activated receptor ␥ (PPAR␥) in vascular endothelial cells in a ligand-dependent manner that involves phospholipase A2 and cytochrome P450 epoxygenases. In this study, we investigated whether epoxyeicosatrienoic acids (EETs), the catalytic products of cytochrome P450 epoxygenases, are PPAR␥ ligands. Competition and direct binding assays revealed that EETs bind to the ligandbinding domain of PPAR␥ with Kd in the M range. In the presence of adamantyl-ureido-dodecanoic acid (AUDA), a soluble epoxide hydrolase (sEH)-specific inhibitor, EETs increased PPAR␥ transcription activity in endothelial cells and 3T3-L1 preadipocytes. Inclusion of AUDA in the perfusing media enhanced, but overexpression of sEH reduced, the laminar flow-induced PPAR␥ activity. Furthermore, laminar flow augmented cellular levels of EETs but decreased sEH at the levels of mRNA, protein, and activity. Blocking PPAR␥ by GW9662 abolished the EET͞AUDA-mediated antiinflammatory effect, which indicates that PPAR␥ is an effector of EETs. endothelial cells ͉ shear stressA therosclerosis preferentially localizes in branches and curved regions of the arterial tree, where the blood flow is disturbed. In contrast, the straight parts of vessels exposed to nondisturbed laminar flow have few lesions (1). The focal distribution of atherosclerotic lesions has been proposed to be related to the proinflammatory effect of disturbed flow imposed on the endothelium vs. the antiinflammatory effect of laminar flow. In vitro studies using flow channels with cultured endothelial cells (ECs) revealed that disturbed flow induces a number of molecules involved in inflammation, including chemoattractants, adhesion molecules, and cytokines (2, 3). However, prolonged exposure to laminar flow suppresses the cytokine-stimulated or oxidized low-density lipoprotein (LDL)-stimulated inflammatory response in ECs (4).Recent studies showed that the nuclear receptor peroxisome proliferator-activated receptor ␥ (PPAR␥) is involved in antiinflammatory effects in the artery wall (5, 6). The activation of PPAR␥ in cultured ECs suppresses the NF-B-mediated expression of molecules such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and endothelin 1 that are involved in the inflammatory response (7,8). Troglitazone, a synthetic PPAR␥ ligand, attenuates the formation of lesions in both apolipoprotein E-and low-density lipoprotein receptordeficient mice (7, 9), due in part to the reduction of monocytes͞ macrophages homing to the plaques.We previously demonstrated that laminar flow activates PPAR␥ in a ligand-dependent manner, which exerts an antiinflammatory effect in ECs. Furthermore, we showed that such induction of PPAR␥ ligands involves phospholipase A2 and cytochrome P450 epoxygenases (CYPs) (10). Epoxyeicosatrienoic acids (EETs), the main products of arachidonic acid catalyzed by CYPs, have been reported to dilate coronary arteries by hyperpolarizing vascular smooth muscles (11) and to exe...
Objective-The regulation of AMP-activated protein kinase (AMPK) is implicated in vascular biology because AMPK can phosphorylate endothelial NO synthase (eNOS). In this study, we investigate the regulation of the AMPK-eNOS pathway in vascular endothelial cells (ECs) by shear stress and the activation of aortic AMPK in a mouse model with a high level of voluntary running (High-Runner). Methods and Results-By using flow channels with cultured ECs, AMPK Thr172 phosphorylation was increased with changes of flow rate or pulsatility. The activity of LKB1, the upstream kinase of AMPK, and the phosphorylation of eNOS at Ser1179 were concomitant with AMPK activation responding to changes in flow rate or pulsatility. The blockage of AMPK by a dominant-negative mutant of AMPK inhibited shear stress-induced eNOS Ser1179 phosphorylation and NO production. Furthermore, aortic AMPK activity and level of eNOS phosphorylation were significantly elevated in the aortas of High-Runner mice. Conclusions-Our results suggest that shear stress activates AMPK in ECs, which contributes to elevated eNOS activity and subsequent NO production. Hence, AMPK, in addition to serving as an energy sensor, also plays an important role in regulating vascular tone. Key Words: endothelium Ⅲ AMPK Ⅲ nitric oxide synthase Ⅲ shear stress Ⅲ exercise E ndothelium-derived NO can enhance vascular functions, including vessel relaxation, survival of vascular endothelial cells (ECs), inhibition of platelet aggregation, and attenuation of leukocyte infiltration. 1,2 Impaired NO bioavailability has been suggested as one of the earliest pathophysiological events preceding endothelial dysfunction and contributing to atherosclerosis. 3,4 Shear stress is an important physiological stimulus that enhances the production of NO by ECs. 2,5 An increase in shear stress such as in exercise augments the EC-mediated bioavailability of NO. 6 Endothelial NO synthase (eNOS), the key enzyme for NO production in ECs, is tightly regulated not only at the transcriptional level but also by several post-translational mechanisms. The enhanced phosphorylation of Ser1179 of bovine eNOS (Ser1177 in humans) leads to increased eNOS activity. Mounting evidence has shown that shear stress enhances the phosphorylation of Ser1177/1179. 7-9 Use of the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin and LY 294002 has demonstrated that Akt phosphorylates eNOS Ser1177/1179 in response to shear stress. 7,8 However, dominant-negative mutants of Akt were unable to block the shear stress-stimulated Ser1179 phosphorylation. 9 Further, H89, a protein kinase A (PKA) inhibitor, and an adenovirusexpressing PKA inhibitor (PKI) blocked the eNOS Ser1179 phosphorylation, which indicates the involvement of PKA. 9 -12 Functioning as a metabolic master switch, AMP-activated protein kinase (AMPK) senses and regulates the cellular energy status in various cell types. AMPK is activated by several physiological and pathological stresses such as exercise, hypoxia, and nutrient depletion that result in incre...
Laminar burning velocities and Markstein lengths of 2,5-dimethylfuran (DMF)-air-N 2 /CO 2 premixed mixtures at the atmospheric pressure and initial temperature of 393 K over three different dilution ratios were obtained by using the outwardly propagating spherical flame and high-speed schlieren photograph system. Addition of diluent was used to simulate the effects of exhaust gas recirculation on the flame propagation. The results show that both unstretched flame propagation speed and laminar burning velocity decrease with the increase of dilution ratio. Markstein length is increased with the increase of dilution ratio, indicating that addition of diluent will improve the stability of the flame. The dilution effects of CO 2 as diluent on the flame propagation and the flame stability are stronger than those of N 2 as diluent. For a specific equivalence ratio, the laminar burning velocity shows a linear decreasing trend with the increase of dilution ratio. The ratio of the laminar burning velocities with and without diluent gas (the normalized laminar burning velocity) demonstrates good linear trend versus the dilution ratio, and a linear formula is developed to express this relationship based on experimental data.
A detailed chemical kinetic mechanism has been developed to describe the pyrolysis and oxidation of the hydrogen/NOx and syngas/NOx systems. The thermodynamic data of nitrogenous compounds have been updated based on the study of Bugler et al. [J. Bugler, K.P. Somers, J.M. Simmie, F. Güthe, H.J. Curran. J. Phys. Chem. A, 2016, 120(36):7192-7197.]. The rate constants of individual elementary reactions associated with the Zeldovich mechanism, the N/O sub-mechanism (NO2, N2O and NO3), the H/N/O sub-mechanism (HNO/HON, HNO2/HONO and HONO2) and the NH3 mechanism (NNH and NH2OH) have been selected through a synthetic comparison of the data available in the literature and the adoption of the latest available published rate constant data. The proposed mechanism has been validated against a large number of experimental data including pyrolysis histories, ignition delay time data, species profile versus time and temperature and flame speed measurements over a wide range of initial combustion conditions and various experimental devices including shock tubes, flow reactors, jet-stirred reactors and spherical combustion bombs.The simulations of the proposed model have also been compared to those from five recently published kinetic models available in the literature. It was found that although these mechanisms generally reproduced well the data for which they were validated, they did not globally capture the combustion characteristics of all of the hydrogen/NOx and syngas/NOx systems.Finally, the proposed model has been used to simulate the formation of NO at practical gas-turbine relevant conditions. A detailed flux analysis has been performed to kinetically explore the NO formation mechanism under various combustion conditions.
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