NAD(P)H oxidase-derived ROS may act as intercellular

regulators of the redox-sensitive transcription factors HIF-1α and Nrf2, and their target genes including NQO1, γ-glutamylcysteine synthetase, and HO-1 [94]. In aortic endothelial cells, advanced glycation end products evoke ROS generation and activate Nrf2-dependent expression of HO-1 and NQO1, providing evidence of adaptive Nrf-2-mediated protection against oxidative stress in diabetes [33]. Increased ROS production by the mitochondria, xanthine oxidase, and uncoupled eNOS may also activate these transcription factors leading to upregulation FDA approved Drug Library concentration of antioxidant enzymes; however, with age the responsiveness of redox-sensitive transcription factors wanes in the aorta and carotid arteries [93,94]. Together, these findings suggest that an age-related decline in the ability to activate endogenous antioxidant mechanisms contributes to increased endothelial inflammation and apoptosis in large arteries. Future work will be needed to determine whether or not the function of endogenous antioxidant defense mechanisms declines in the microvascular endothelium with advancing age. The impact of an age-related decline in endogenous antioxidant mechanisms on angiogenesis, endothelium-dependent vasodilation, and microvascular permeability remains to be assessed in the microvasculature. In contrast to O2•−,

H2O2 is not a free radical (i.e., unpaired electrons on an open shell configuration), making it less reactive, more stable and longer lasting [2]. These properties and the ability of H2O2 to diffuse across cell membranes allow it to play an important AZD1208 clinical trial signaling role. H2O2 is primarily produced by the dismutation of O2•− by SOD, but can also be formed by the spontaneous dismutation of O2•−, or directly by the action of enzymes such as xanthine oxidase, glucose oxidase [7], and NADPH oxidase [17,51,72,76]. H2O2 is found in both physiological and pathophysiological states. In aging, H2O2 production is increased [13,48]

possibly due to age-related increases in mitochondrial H2O2 generation [79–81] and eNOS dependent O2•− generation [4]. H2O2 does not inactivate NO• and in conditions Teicoplanin of oxidant stress, H2O2 may act as a compensatory mechanism to maintain NO• bioavailability. H2O2 has been shown to cause a potent dose-dependent increase in NO• production [9], upregulate eNOS expression [8,19], and to enhance eNOS function by promoting eNOS phosphorylation and eNOS dephosphorylation at Thr-495 [90]. Recently, Martin-Garrido et al. [50] demonstrated that H2O2 enhances vascular relaxation to NO by stabilizing sGCβ1 mRNA through HuR, increasing the expression of sGCβ1 and thus increasing cGMP formation. However, Gerassimou et al. [27] showed that higher concentrations of H2O2 downregulated sGCα1 mRNA indicating that the levels of H2O2 may dictate its action.