Gene transfer of human guanosine 5'-triphosphate cyclohydrolase I restores vascular tetrahydrobiopterin level and endothelial function in low renin hypertension.
BACKGROUND
We recently reported that arterial superoxide (O2-) is augmented by increased endothelin-1 (ET-1) in deoxycorticosterone acetate (DOCA)-salt hypertension, a model of low renin hypertension. Tetrahydrobiopterin (BH4), a potent reducing molecule with antioxidant properties and an essential cofactor for endothelial nitric oxide synthase, protects against O2--induced vascular dysfunction. However, the interaction between O2- and BH4 on endothelial function and the underlying mechanisms are unknown.


RESULTS
The present study tested the hypothesis that BH4 deficiency due to ET-1-induced O2- leads to impaired endothelium-dependent relaxation and that gene transfer of human guanosine 5'-triphosphate (GTP) cyclohydrolase I (GTPCH I), the first and rate-limiting enzyme for BH4 biosynthesis, reverses such deficiency and endothelial dysfunction in carotid arteries of DOCA-salt rats. There were significantly increased arterial O2- levels and decreased GTPCH I activity and BH4 levels in DOCA-salt compared with sham rats. Treatment of arteries of DOCA-salt rats with the selective ETA receptor antagonist ABT-627, NADPH oxidase inhibitor apocynin, or superoxide dismutase (SOD) mimetic tempol abolished O2- and restored BH4 levels. Basal arterial NO release and endothelium-dependent relaxations were impaired in DOCA-salt rats, conditions that were improved by apocynin or tempol treatment. Gene transfer of GTPCH I restored arterial GTPCH I activity and BH4 levels, resulting in reduced O2- and improved endothelium-dependent relaxation and basal NO release in DOCA-salt rats.


CONCLUSIONS
These results indicate that a BH4 deficiency resulting from ET-1-induced O2- via an ETA/NADPH oxidase pathway leads to endothelial dysfunction, and gene transfer of GTPCH I reverses the BH4 deficiency and endothelial dysfunction by reducing O2- in low renin mineralocorticoid hypertension.
Zheng
Jie-Sheng
JS
Department of Pharmacology and Toxicology and the Neuroscience Program, B403 Life Sciences Building, Michigan State University, East Lansing, Mich 48824-1317, USA.
Yang
Xiang-Qun
XQ
Lookingland
Keith J
KJ
Fink
Gregory D
GD
Hesslinger
Christian
C
Kapatos
Gregory
G
Kovesdi
Imre
I
Chen
Alex F
AF
D000098:Acetophenones / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D000077868:Atrasentan; D001708:Biopterins / Q000031:analogs & derivatives* / Q000172:deficiency / Q000378:metabolism*; D002339:Carotid Arteries / Q000187:drug effects / Q000503:physiopathology; D003497:Cyclic N-Oxides / Q000627:therapeutic use; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006136:GTP Cyclohydrolase / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology / Q000628:therapy*; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D012965:Sodium Chloride; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D000098:Acetophenones; D000975:Antioxidants; D003497:Cyclic N-Oxides; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D013113:Spin Labels; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; D003900:Desoxycorticosterone; D012965:Sodium Chloride; C056165:acetovanillone; D006136:GTP Cyclohydrolase; C003402:sapropterin; C001803:tempol; D000077868:Atrasentan