Redox-Sensitive Oxidation and Phosphorylation of PTEN Contribute to Enhanced Activation of PI3K/Akt Signaling in Rostral Ventrolateral Medulla and Neurogenic Hypertension in Spontaneously Hypertensive Rats

Abstract

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.

The phosphoinositide‐3 kinase signaling is involved in neuroinflammation in hypertensive rats

“…It is reported that the activity of the PI3K/AKT pathway is enhanced in the RVLM of SHR, and the phosphorylation of AKT in the PVN of hypertensive rats is also increased . Recently, we also confirmed that an inactivation of PI3K signaling in the RVLM is involved in antioxidative stress induced by central antihypertensive mechanism .…”

“…Previous evidence suggests that the phosphoinositide‐3 kinase (PI3K) pathway in the RVLM is involved in regulating BP and sympathetic outflow . It has been demonstrated that the PI3K signaling in the RVLM is upregulated in hypertension, and its inactivation leads to reduction in reactive oxygen species (ROS) production and cardiovascular function . Moreover, we recently report that gene knockdown of the PI3K subunit p110δ in the RVLM exerts the centrally antihypertensive action …”

Withaferin A induces Nrf2-dependent protection against liver injury: Role of Keap1-independent mechanisms

“…Furthermore, overexpression of antioxidant enzymes such as SOD and catalase have been associated with production of H 2 O 2 and activated Akt signaling mediated by oxidized Pten [72]. The redox-sensitive interplay between Pten and Pi3k signaling is also involved in the pathogenesis of conditions such as hypertension [73]. Age-dependent down regulation of Pi3k signaling is associated with increased susceptibility to oxidative stress [74].…”

Redox signaling in pathophysiology of hypertension

“…In myocardium, Akt kinase has been considered as a reperfusion injury salvage kinase, counteracting oxidative stress-induced cell damage through a compensatory protective pathway [65]. In the RVLM of brain stem, ROS activates PI3K/Akt signaling via oxidation and phosphorylation of the phosphatase and tensin homolog deleted on chromosome 10, which is a negative regulator of PI3K signaling [66]. This redox-sensitive overactivation of PI3K/Akt signaling contributes to neural mechanisms of hypertension in SHR.…”