Endothelium-specific GTP cyclohydrolase I overexpression attenuates blood pressure progression in salt-sensitive low-renin hypertension.
BACKGROUND
Tetrahydrobiopterin (BH4) is an essential cofactor of endothelial nitric oxide synthase (eNOS). When BH4 levels are decreased, eNOS becomes uncoupled to produce superoxide anion (O2(-)) instead of NO, which contributes to endothelial dysfunction. Deoxycorticosterone acetate (DOCA)-salt hypertension is characterized by a suppressed plasma renin level due to sodium retention but manifests in eNOS uncoupling; however, how endogenous BH4 regulates blood pressure is unknown. GTP cyclohydrolase I (GTPCH I) is the rate-limiting enzyme for de novo BH4 synthesis. This study tested the hypothesis that endothelium-specific GTPCH I overexpression retards the progression of hypertension through preservation of the structure and function of resistance mesenteric arteries.


RESULTS
During 3 weeks of DOCA-salt treatment, arterial blood pressure was increased significantly in wild-type mice, as determined by radiotelemetry, but this increase was attenuated in transgenic mice with endothelium-specific GTPCH I overexpression (Tg-GCH). Arterial GTPCH I activity and BH4 levels were decreased significantly in wild-type DOCA-salt mice, but both were preserved in Tg-GCH mice despite DOCA-salt treatment. Significant remodeling of resistance mesenteric arteries (approximately 100-microm outside diameter) in wild-type DOCA-salt mice exists, evidenced by increased medial cross-sectional area, media thickness, and media-lumen ratio and overexpression of tenascin C, an extracellular matrix glycoprotein that contributes to hypertrophic remodeling; all of these effects were prevented in DOCA-salt-treated Tg-GCH mice. Furthermore, NO-mediated relaxation in mesenteric arteries was significantly improved in DOCA-salt-treated Tg-GCH mice, in parallel with reduced O2(-) levels. Finally, phosphorylation of eNOS at serine residue 1177 (eNOS-S1177), but not its dimer-monomer ratio, was decreased significantly in wild-type DOCA-salt mice compared with sham controls but was preserved in DOCA-salt-treated Tg-GCH mice.


CONCLUSIONS
These results demonstrate that endothelium-specific GTPCH I overexpression abrogates O2(-) production and preserves eNOS phosphorylation, which results in preserved structural and functional integrity of resistance mesenteric arteries and lowered blood pressure in low-renin hypertension.
Du
Yan-Hua
YH
Department of Pharmacology, Michigan State University, East Lansing, USA.
Guan
Yong-Yuan
YY
Alp
Nicholas J
NJ
Channon
Keith M
KM
Chen
Alex F
AF
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight; D003331:Coronary Vessels / Q000502:physiology; D003900:Desoxycorticosterone; D004730:Endothelium, Vascular / Q000201:enzymology*; D006136:GTP Cyclohydrolase / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008901:Mineralocorticoids; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D017382:Reactive Oxygen Species / Q000378:metabolism; D012083:Renin / Q000097:blood*; D012965:Sodium Chloride; D019063:Tenascin / Q000378:metabolism; D014655:Vascular Resistance / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
D008901:Mineralocorticoids; D017382:Reactive Oxygen Species; D019063:Tenascin; D001708:Biopterins; D009569:Nitric Oxide; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D012083:Renin; D006136:GTP Cyclohydrolase; C003402:sapropterin