Journal of Signal Transduction H2O2 leads to airway smooth muscle contraction mediated by increases in intracellular Ca2+ concentration and the Rho/Rho kinase pathway [77]. Both ROS and Rho/Rho kinase have been suggested to play important roles in vasoconstriction and may contribute to the pathogenesis of hypertension in experimental animals and humans. Jin and coworkers demonstrated the direct activation of the Rho/Rho kinase signaling pathway by ROS in rat aorta, suggesting an important role for ROS-mediated Rho/Rho kinase activation in vasoconstriction [78]. As previously discussed, Aghajanian and coworkers pro- posed a novel mechanism for the regulation of RhoA in cells by ROS that allows predicting that ROS may directly activate Rho signaling in smooth muscle and in the endothelium thus aﬀecting vascular permeability. This mechanism of regula- tion, which is independent of classical regulatory proteins, may be particularly relevant in pathological conditions where ROSs are generated and the cellular redox-balance altered, such as in asthma and I/R injury [62]. It is well known that activated Ras signaling contributes to oncogenic transformation by providing molecular signals that promote cell proliferation, obstruct cell death, inhibit cellular diﬀerentiation, and induce angiogenesis [79]. Sig- naling pathways starting from activated Ras and resulting in mitochondrial ROS production and downstream signaling regulation have been the subject of several recent interesting studies, and diﬀerent mechanisms have been proposed to elucidate the role of mitochondrial respiration in cancer. It has been shown that the activation of K-Ras(G12V) causes modiﬁcations in mitochondrial metabolism ﬁnalized to support growth under hypoxic conditions, and leading to increased generation of ROS [80]. The major source of ROS generation required for KRas-induced anchorage- independent growth is the Qo site of mitochondrial complex III [81]. Thus mitochondrial dysfunction appears to be an important mechanism by which K-Ras(G12V) causes met- abolic changes and ROS stress in cancer cells and promotes tumor development [80]. Mitochondrial dysfunction and ROS production medi- ated by activation of Ras, Myc, and p53 produce downstream signaling (e.g., NFκB, STAT3, etc.) that are crucial in cancer- related inﬂammation. Diﬀerent inﬂammation-associated cancers resulting from signaling pathways coordinated at the mitochondrial level have been identiﬁed that may prove useful for developing innovative strategies for both cancer prevention and cancer treatment [82]. Several studies suggest that autophagy may be important in the regulation of cancer development and progression and in determining the response of tumor cells to anticancer therapy [83]. A recent paper shows that autophagy is associated with the malignant transformation of mammalian cells induced by K-Ras and that ROSs are involved as sig- naling molecules in K-Ras(G12V)-induced autophagy. The increase in intracellular ROS produced in response to on- cogenic K-Ras involves p38 MAPK signaling and leads to JNK activation. JNK acts downstream of ROS and plays a causal role in autophagy induction through upregulation of autophagy-speciﬁc genes 5 and 7 (ATG5 and ATG7) [84]. As mitochondria sustain viability of Ras-expressing cells in 5 starvation, autophagy is required to maintain the pool of functional mitochondria necessary to support growth of Ras- driven tumors [85]. These ﬁndings provide new insights into the relationship between autophagy and oncogenesis and suggest that targeting autophagy and mitochondrial metabolism are valuable new approaches to treat cancers with Ras mutations. Oncogenic activation of the H-Ras gene has been found in more than 35% of patients with urothelial carcinomas [86]. It has been recently shown that in addition to tu- morigenic ability, oncogenic H-Ras possesses a novel proap- optotic activity to facilitate the induction of apoptosis by histone deacetilase inhibitors (HDACIs), a new class of an- ticancer agents characterized by high cytotoxicity toward transformed cells [87]. Expression of oncogenic H-Ras in human bladder tumor J82 cells and treatment of cells with the HDACI, FK228, sinergistically induce the ERK pathway, resulting in diﬀerentially increased NOX-1 elevation and ROS production, leading to diﬀerential activation of caspases and cell death [88–90]. Thus, in addition to its well-known role in mediating mitogenic signals for cell proliferation and transformation, the ERK pathway plays an essential role in mediating apoptotic signals induced by HDACIs through induction of NOX-1 elevation to ROS production and caspase activation for inducing cell death. In addition, expression of oncogenic H-Ras in J82 cells also results in an increased susceptibility to exogenous H2O2 for inducing cas- pase activation and apoptosis [88]. Further studies revealed that FK228 combined with exogenous H2O2 cooperatively induces activation of MEK1/2 and ERK1/2 to increase NOX- 1 elevation, intracellular ROS production, caspase activa- tion, and cell death. Expression of oncogenic H-Ras sig- niﬁcantly increases these FK288- and exogenous H2O2- induced eﬀects. Oncogenic H-Ras-increased susceptibility to FK228 could be alternatively achieved by additional treat- ment with exogenous H2O2. These ﬁndings have important and useful implications as combined use of HDACIs with ROS-generating agents may apply to therapeutic strategies to preferentially kill malignant cells with or without oncogenic H-Ras activation [91]. Due to the crucial role played by Ras in many cellular signaling cascades, diseases relevant to dysregulation of redox signaling often result in deregulation of Ras-dependent cel- lular signaling events. Since the ﬁrst identiﬁcation of the redox-sensitive NKCD motif of Ras [51], considerable patho- physiological data are available, including some bearing directly on the relevance of redox-mediated misregulation of the Ras NKCD motif to certain diseases [7]. Rap1A, another reprehensive protein that possesses the NKCD-motif, is a reg- ulator of NAD(P)H oxidase. However, a pathophysiological outcome associated with the misregulation of Rap1A redox signaling has not been clearly investigated [7]. Cancer is one of the most prevalent disorders caused by misregulation of Ras activity by a redox agent. Numerous studies show that cancers, to a large extent, are induced by misregulation of Ras redox signaling combined with an alteration of Ras downstream cellular transduction cascades. As with cancers, many cardiovascular and neuronal disorders