Numerous studies in animal models and human subjects corroborate that elevated levels of reactive oxygen species (ROS) play a pivotal role in the progression of multiple diseases. promise as targeted therapeutics. Increased insight into the mechanisms of action and regulation of this family of enzymes as well as atomic structures of key Nox subunits are expected to give way to a broader spectrum of more potent efficacious and specific molecules. These lead molecules will assuredly serve as a basis for drug development aimed at treating a wide array of diseases associated with increased Nox activity. 20 2741 Introduction Oxidative stress is manifested by a shift Almotriptan malate (Axert) in the steady-state balance between the production of reactive oxygen or nitrogen species (ROS/RNS) and the antioxidant reserves of a biological system. When the proper cellular redox homeostasis is maintained low levels of ROS evidently play an essential role as second messengers in myriad inter- and intracellular signaling cascades regulating neuronal signaling blood pressure and balance (52 133 However following a shift toward an increasingly pro-oxidant state cells may succumb to an inexorable impairment of function and damage as a consequence of excessive protein and lipid oxidation and DNA damage. Among the leading causes of death that afflict the U.S. population (72) cardiovascular diseases neurodegenerative disorders and cancer appear to share oxidative stress as a common nexus (18). Excessive and unabated levels of ROS have been shown to play a key role in the pathophysiology of cardiovascular diseases such as hypertension (6 53 99 115 160 atherosclerosis (149) cardiac hypertrophy (14) stroke (82) and conditions including ischemia reperfusion (110) and restenosis (76 104 Moreover the neurodegenerative Huntington’s (164) Alzheimer’s (9) and Parkinson’s diseases have augmented ROS implicated in their etiology (27 154 Further evidence for the involvement of ROS in the progression of carcinogenesis is also demonstrated (172). Indeed ROS can lead to oxidation of DNA resulting in gene Almotriptan malate (Axert) mutations duplication and activation of oncogenes (87). However physiological ROS levels are demonstrated to regulate signaling pathways (52 133 thiol modification of redox-sensitive proteins resulting in conformational changes that alter enzymatic activity (kinases and phosphatases involved in growth factor signaling) or DNA binding of activated transcription factors such as NFκB and AP-1 (129 176 The main cellular defense mechanisms that protect against increased ROS levels are antioxidant enzymes such as superoxide dismutase catalase glutathione peroxidases and thioredoxin as well Rabbit polyclonal to AACS. as dietary scavengers including α-tocopherol and ascorbic acid (52). Importantly their roles in the neutralization of ROS derived from cellular respiration and other enzymatic sources Almotriptan malate (Axert) such as xanthine oxidase uncoupled NO synthase and most important to this review NADPH oxidase (Nox) are well established (47). Under normal homeostatic conditions organ systems utilize these antioxidant systems Almotriptan malate (Axert) to maintain the redox balance. Increasing evidence demonstrates Nox as a main cellular source of ROS playing an important role in ROS-dependent signaling cascades (20 98 Moreover it is becoming increasingly evident that augmented ROS production by the Nox family of proteins promotes activation and upregulation of Nox isoforms in a “feed-forward” mechanism further contributing to oxidative stress and disease progression (40 98 Nox Family of Proteins Nox enzymes belong to a closely related family of membrane proteins that catalyze the production of superoxide anion and/or hydrogen peroxide by electron transfer from NADPH to molecular oxygen heme groups in their transmembrane domains Almotriptan malate (Axert) utilizing FAD as a cofactor. To date seven members of the Nox family have been identified namely Nox1 Nox2 Nox3 Nox4 Nox5 Duox1 and Duox2. The isoforms differ in their subunit composition activation physiological and pathophysiological functions and in their subcellular and tissue expression (25 92 (Table 1). For more extensive details on the structure and activation of Nox isoforms please refer to previous reviews (2 13 59 66 103 152 The most well-studied Nox isozyme to date is the respiratory burst enzyme Nox2 (gp91(organizer subunit) p67(activator subunit) and p40and in its canonical conformation is regulated by cytosolic NOXO1 organizer (homologous to p47and can be regulated by NOXA1 and NOXO1 but also by p47and p67(26 163 Nox4 on the other hand does require p22but the only other known regulator described for it is Poldip2. Nox5 distinct from Nox1-4 does not require p22and is regulated by.