Α-lipoic Acid Reduces Neurogenic Hypertension by Blunting

22 We previously reported that ACE2 compensatory activity is impaired by the 23 disintegrin and metalloprotease 17 (ADAM17) and lack of ACE2 is associated 24 with oxidative stress in neurogenic hypertension. To investigate the relationship 25 between ADAM17 and oxidative stress, Neuro2A cells were treated with Ang-II 26 (100 nM) 24 h after vehicle or α-lipoic acid (LA: 500 μM). ADAM17 expression 27 was increased by Ang-II (120.5 ±9.1 vs. 100.2 ±0.8%, P<0.05) and decreased 28 after LA (69.0 ±0.3 vs. 120.5 ±9.1%, P<0.05). In other set of experiments, LA 29 reduced ADAM17 (92.9 ±5.3 vs. 100.0 ±11.2%, P<0.05) following its 30 overexpression. Moreover, ADAM17 activity was reduced by LA in ADAM1731 overexpressing cells (109.5 ±19.8 vs. 158.0 ±20.0 FU/min/μg protein, P<0.05), 32 in which ADAM17 overexpression increased oxidative stress (114.1 ±2.5 vs. 33 101.0 ±1.0%, P<0.05). Conversely, LA-treated cells attenuated ADAM17 34 overexpression-induced oxidative stress (76.0 ±9.1 vs. 114.1 ±2.5%, P<0.05). 35 In DOCA-salt-hypertensive mice, a model in which ADAM17 expression and 36 activity are increased, hypertension was blunted by pre-treatment with LA 37 (119.0 ±2.4 vs. 131.4 ±2.2 mmHg, P<0.05). In addition, LA improved 38 dysautonomia and baroreflex sensitivity. Furthermore, LA blunted the increase 39 in NADPH oxidase subunits expression, as well as the increase in ADAM17 and 40 decrease in ACE2 activity in the hypothalamus of DOCA-salt hypertensive mice. 41 Taken together, these data suggest that LA might preserve ACE2 42 compensatory activity by breaking the feed-forward cycle between ADAM17 43 and oxidative stress, resulting in a reduction of neurogenic hypertension. 44