Bcl 2 increases GSH levels and functions as an antioxidant

in close agreement with previously published that demonstrated the efficacy of NO inhibitors or endothelial removal in preventing low dose but not high dose nitroglycerin induced vasodilation. Not surprisingly, obvious aftereffects of GTN in decreasing diastolic blood pressure in rats were markedly reduced once the animals were pretreated with checkpoint inhibitors wortmannin or Akt inhibitor. Taken together, these represent compelling evidence implicating signal transduction pathways in the mediation of GTNs pharmacological effects by causing eNOS. Certainly, studies performed with endothelial cells and shown in Fig. 4 demonstrated that 0. 5 uM GTN immediately induced the phosphorylation of eNOS in the site Ser 1177, which was completely inhibited by both PI3K or Akt inhibitor. These reports were recapitulated in human endothelial microvascular cells. In both BAEC and HMEC, eNOS phosphorylation was temporally paralleled by Akt activation, showing the involvement of the pathway in GTN induced activation. Apparently, we also found Plastid that PTEN, the enzyme that opposes PI3K activity by degrading InsP3, was rapidly inhibited by GTN. PTEN inhibition was determined through the Western blot analysis of the inhibitory site Ser 380 phosphorylation and through the quantification of the energetic second messenger InsP3. PTEN inhibition was more confirmed by the measurement of PTEN exercise after immunopurification from lysates of cells previously exposed to GTN. Essentially, PTEN lipid phosphatase activity is dependent on the critical active deposit Cys 124. In its paid off form the low pKa Cys 124 thiolate catalyzes the elimination of HCV Protease Inhibitors the 3 phosphate group of phosphatidylinositol in remarkable similarity to the proposed and widely-accepted procedure of ALDH 2 inhibition by GTN. Nevertheless, different from ALDH 2, which is confined in mitochondria, PTEN, which is itself fairly sensitive and painful to inhibition by oxidants and by electrophiles, exists mainly in the cytosol, especially at the vicinity of the plasma membrane, and is thus more likely to communicate with diffusible xenobiotics upon their entry into the cell. Certainly, the fundamental role of ALDH 2 in GTN bio-conversion to NO was claimed largely on the basis of knockout studies that showed that ALDH 2 knockout animals are less responsive to low dose GTN than ALDH 2 competent animals. Nonetheless, depletion of ALDH 2 has been related to increased oxidative stress and vascular dysfunction probably due to increased levels of reactive species production. Thus, with the currently available data it's impossible to tell apart whether the GTN tolerant phenotype exhibited by the ALDH 2 knockout animal is a consequence of its inability to transform GTN to NO or, instead, is due to dysregulation of oxidant delicate signal transduction pathways including the PI3K/Akt/PTEN axis.