Glutathione-S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke.
Exposure to tobacco smoke impairs endothelium-dependent arterial dilation. Reactive constituents of cigarette smoke are metabolized and detoxified by glutathione-S-transferases (GSTs). Although polymorphisms in GST genes are associated with the risk of cancer in smokers, the role of these enzymes in regulating the cardiovascular effects of smoking has not been studied. The P isoform of GST (GSTP), which catalyzes the conjugation of electrophilic molecules in cigarette smoke such as acrolein, was expressed in high abundance in the mouse lung and aorta. Exposure to tobacco smoke for 3 days (5 h/day) decreased total plasma protein. These changes were exaggerated in GSTP(-/-) mice. Aortic rings isolated from tobacco smoke-exposed GSTP(-/-) mice showed greater attenuation of ACh-evoked relaxation than those from GSTP(+/+) mice. The lung, plasma, and aorta of mice exposed to tobacco smoke or acrolein (for 5 h) accumulated more acrolein-adducted proteins than those tissues of mice exposed to air, indicating that exposure to tobacco smoke results in the systemic delivery of acrolein. Relative to GSTP(+/+) mice, modification of some proteins by acrolein was increased in the aorta of GSTP(-/-) mice. Aortic rings prepared from GSTP(-/-) mice that inhaled acrolein (1 ppm, 5 h/day for 3 days) or those exposed to acrolein in an organ bath showed diminished ACh-induced arterial relaxation more strongly than GSTP(+/+) mice. Acrolein-induced endothelial dysfunction was prevented by pretreatment of the aorta with N-acetylcysteine. These results indicate that GSTP protects against the endothelial dysfunction induced by tobacco smoke exposure and that this protection may be related to the detoxification of acrolein or other related cigarette smoke constituents.
Conklin
Daniel J
DJ
Institute of Molecular Cardiology, Div. of Cardiovascular Medicine, Dept. of Medicine, Univ. of Louisville, Delia Baxter Bldg., 580 S. Preston St., Rm. 421C, Louisville, KY 40202, USA. dj.conklin@louisville.edu
Haberzettl
Petra
P
Prough
Russell A
RA
Bhatnagar
Aruni
A
D000109:Acetylcholine / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000171:Acrolein / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D001798:Blood Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D051549:Glutathione S-Transferase pi / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology; D014026:Nicotiana
D000975:Antioxidants; D001798:Blood Proteins; D012906:Smoke; D014665:Vasodilator Agents; D009599:Nitroprusside; D000171:Acrolein; D051549:Glutathione S-Transferase pi; C496557:Gstp1 protein, mouse; D000109:Acetylcholine; D000111:Acetylcysteine