α-Lipoic acid reduces neurogenic hypertension by blunting oxidative stress-mediated increase in ADAM17.

We previously reported that type 2 angiotensin-converting enzyme (ACE2) compensatory activity is impaired by the disintegrin and metalloprotease 17 (ADAM17), and lack of ACE2 is associated with oxidative stress in neurogenic hypertension. To investigate the relationship between ADAM17 and oxidative stress, Neuro2A cells were treated with ANG II (100 nM) 24 h after vehicle or α-lipoic acid (LA, 500 µM). ADAM17 expression was increased by ANG II (120.5 ± 9.1 vs. 100.2 ± 0.8%, P < 0.05) and decreased after LA (69.0 ± 0.3 vs. 120.5 ± 9.1%, P < 0.05). In another set of experiments, LA reduced ADAM17 (92.9 ± 5.3 vs. 100.0 ± 11.2%, P < 0.05) following its overexpression. Moreover, ADAM17 activity was reduced by LA in ADAM17-overexpressing cells [109.5 ± 19.8 vs. 158.0 ± 20.0 fluorescence units (FU)·min(-1)·µg protein(-1), P < 0.05], in which ADAM17 overexpression increased oxidative stress (114.1 ± 2.5 vs. 101.0 ± 1.0%, P < 0.05). Conversely, LA-treated cells attenuated ADAM17 overexpression-induced oxidative stress (76.0 ± 9.1 vs. 114.1 ± 2.5%, P < 0.05). In deoxycorticosterone acetate (DOCA)-salt hypertensive mice, a model in which ADAM17 expression and activity are increased, hypertension was blunted by pretreatment with LA (119.0 ± 2.4 vs. 131.4 ± 2.2 mmHg, P < 0.05). In addition, LA improved dysautonomia and baroreflex sensitivity. Furthermore, LA blunted the increase in NADPH oxidase subunit expression, as well as the increase in ADAM17 and decrease in ACE2 activity in the hypothalamus of DOCA-salt hypertensive mice. Taken together, these data suggest that LA might preserve ACE2 compensatory activity by breaking the feedforward cycle between ADAM17 and oxidative stress, resulting in a reduction of neurogenic hypertension.

ADAM17-Mediated Shedding of Inflammatory Cytokines in Hypertension.

The increase of Angiontesin-II (Ang-II), one of the key peptides of the renin-angiotensin system (RAS), and its binding to the Ang-II type 1 receptor (AT1R) during hypertension is a crucial mechanism leading to AD\AM17 activation. Among the reported membrane anchored proteins cleaved by ADAM17, immunological cytokines (TNF-α, IFN-γ, TGF-ß, IL-4, IL-10, IL-13, IL-6, FKN) are the major class of substrates, modulation of which triggers inflammation. The rise in ADAM17 levels has both central and peripheral implications in inflammation-mediated hypertension. This narrative review provides an overview of the role of ADAM17, with a special focus on its cellular regulation on neuronal and peripheral inflammation-mediated hypertension. Finally, it highlights the importance of ADAM17 with regards to the biology of inflammatory cytokines and their roles in hypertension.

Angiotensin-II-derived reactive oxygen species on baroreflex sensitivity during hypertension: new perspectives.

Hypertension is a multifactorial disorder, which has been associated with the reduction in baroreflex sensitivity (BRS) and autonomic dysfunction. Several studies have revealed that increased reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase, following activation of type 1 receptor (AT1R) by Angiotensin-(Ang) II, the main peptide of the Renin-Angiotensin-Aldosterone System (RAAS), is the central mechanism involved in Ang-II-derived hypertension. In the present review, we will discuss the role of Ang II and oxidative stress in hypertension, the relationship between the BRS and the genesis of hypertension and how the oxidative stress triggers baroreflex dysfunction in several models of hypertension. Finally, we will describe some novel therapeutic drugs for improving the BRS during hypertension.