title: α-Lipoic acid reduces neurogenic hypertension by blunting oxidative stress-mediated increase in ADAM17.
abstract: 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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana; Department of Biotechnology, Federal University of Paraíba, João Pessoa, PB, Brazil.
authors.forename: Thyago M
authors.initials: TM
authors.lastname: de Queiroz
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana; Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana; and.
authors.forename: Huijing
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana; Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana; and.
authors.forename: Catalin M
authors.initials: CM
authors.lastname: Filipeanu
authors.affiliation: Department of Biotechnology, Federal University of Paraíba, João Pessoa, PB, Brazil.
authors.forename: Valdir A
authors.initials: VA
authors.lastname: Braga
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana; Neurosciences Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana; Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana; and elazar@lsuhsc.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Lazartigues
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D017704:Baroreflex; D045744:Cell Line, Tumor; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism*; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D000804:Angiotensin II; D008063:Thioctic Acid; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
keywords: antioxidant; deoxycorticosterone acetate-salt hypertension; metalloprotease 17; type 2 angiotensin-converting enzyme