Rationale: Mitochondrial uncoupling proteins (UCPs) belong to a superfamily of mitochondrial anion transporters that uncouple ATP synthesis from oxidative phosphorylation and mitigates mitochondrial reactive oxygen species production. Objective: We assessed the hypothesis that UCP2 participates in central cardiovascular regulation by maintaining reactive oxygen species homeostasis in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons that maintain vasomotor tone located. We also elucidated the molecular mechanisms that underlie transcriptional upregulation of UCP2 in response to oxidative stress in RVLM. Key Words: uncoupling proteins Ⅲ mitochondrion Ⅲ peroxisome proliferator-activated receptor Ⅲ oxidative stress Ⅲ blood pressure L iving organisms possess a variety of physiological protective mechanisms to counteract oxidative stress and to restore redox balance. Oxidative damage to cells that results from an imbalance of production over degradation of the reactive oxygen species (ROS), particularly superoxide anion (O 2 Ϫ⅐ ) and hydrogen peroxide (H 2 O 2 ), is associated with a variety of cardiovascular diseases, including heart failure, atherosclerosis, and hypertension. 1-3 Of note is that overproduction of O 2 Ϫ⅐ and H 2 O 2 in the central nervous system contributes to neural mechanisms of hypertension by increasing sympathetic outflow to the peripheral blood vessels. 4,5 In addition to the degradative enzymes (eg, superoxide dismutase [SOD] and catalase) and low-molecular-weight antioxidants (eg, ascorbic acid and glutathione), the uncoupling proteins (UCPs) have emerged as important natural antioxidants in the maintenance of ROS homeostasis. 6 UCPs belong to a superfamily of mitochondrial anion transporters that uncouple ATP synthesis from oxidative phosphorylation by causing proton leakage across the mitochondrial inner membrane, leading to energy dissipation and heat production. 7 More importantly, the resultant decrease in proton electrochemical gradient across the inner mitochondrial membrane elicited by the UCPs mitigates mitochondrial ROS production. 6,8 In mammals, 5 homologues, UCP1 to UCP5, have so far been cloned. 9 Among them, dysfunction of UCP2 is suggested to be of considerable importance in cardiovas- Methods and Results

Aims: The activity of phosphoinositide 3-kinase (PI3K)/serine/threonine protein kinase (Akt) is enhanced under hypertension. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of PI3K signaling, and its activity is redox-sensitive. In the rostral ventrolateral medulla (RVLM), which is responsible for the maintenance of blood pressure, oxidative stress plays a pivotal role in neurogenic hypertension. The present study evaluated the hypothesis that redox-sensitive inactivation of PTEN results in enhanced PI3K/ Akt signaling in RVLM, leading to neurogenic hypertension. Results: Compared to age-matched normotensive Wistar-Kyoto (WKY) rats, PTEN inactivation in the form of oxidation and phosphorylation were greater in RVLM of spontaneously hypertensive rats (SHR). PTEN inactivation was accompanied by augmented PI3K activity and PI3K/Akt signaling, as reflected by the increase in phosphorylation of Akt and mammalian target of rapamycin. Intracisternal infusion of tempol or microinjection into the bilateral RVLM of adenovirus encoding superoxide dismutase significantly antagonized the PTEN inactivation and blunted the enhanced PI3K/Akt signaling in SHR. Gene transfer of PTEN to RVLM in SHR also abrogated the enhanced Akt activation and promoted antihypertension. Silencing PTEN expression in RVLM with small-interfering RNA, on the other hand, augmented PI3K/Akt signaling and promoted long-term pressor response in normotensive WKY rats.Innovation: The present study demonstrated for the first time that the redox-sensitive check-and-balance process between PTEN and PI3K/Akt signaling is engaged in the pathogenesis of hypertension. Conclusion: We conclude that an aberrant interplay between the redox-sensitive PTEN and PI3k/Akt signaling in RVLM underpins neural mechanism of hypertension. Antioxid. Redox Signal. 18, 36-50.