Growth hormone treatment improves markers of systemic nitric oxide bioavailability via insulin-like growth factor-I.
OBJECTIVE
Impaired nitric oxide (NO) bioavailability and low levels of circulating endothelial progenitor cells (EPC) are correlated to an increased risk for development of cardiovascular diseases. We investigated whether improved systemic NO bioavailability and increased levels of EPC after GH treatment are related and mediated by the IGF-I.
Healthy middle-aged volunteers (n = 16) were treated for 10 d with recombinant human GH. Before and after GH treatment, we analyzed markers of NO bioavailability and EPC levels. GH treatment was responded by significant increases in plasma IGF-I levels. Urinary cGMP levels were increased and diastolic blood pressure reduced after GH treatment (P < 0.05). Likewise, plasma nitrate and nitrite levels were increased, whereas the NO synthase inhibitor asymmetric dimethylarginine was reduced. Correspondingly, IGF-I treatment increased expression of the asymmetric dimethylarginine-metabolizing enzyme dimethylarginie dimethylaminohydrolase-1 and dimethylarginie dimethylaminohydrolase-2 in cultured human endothelial cells. IGF-I levels correlated with cGMP concentrations (r = 0.51; P < 0.05). EPC numbers were increased after GH treatment and correlated with markers for NO bioavailability. These findings were also observed in mice treated with GH for 7 d. GH treatment additionally increased aortic endothelial NO synthase expression of mice. Importantly, blocking of the IGF-I receptor in vivo abolished the GH-mediated effects on markers of increased NO bioavailability.


CONCLUSIONS
GH treatment induced markers of increased NO bioavailability and enhanced circulating EPC numbers in healthy volunteers. Animal data demonstrate increased NO availability to be mediated via an increase in IGF-I plasma levels. Thus, GH treatment enhances systemic NO bioavailability via IGF-I and may be beneficial in certain cardiovascular diseases.
Thum
Thomas
T
Universitätsklinikum, Medizinische Klinik I (Kardiologie), 97080 Würzburg, Germany. thum_t@klinik.uni-wuerzburg.de
Fleissner
Felix
F
Klink
Ivonne
I
Tsikas
Dimitrios
D
Jakob
Marten
M
Bauersachs
Johann
J
Stichtenoth
Dirk O
DO
D000368:Aged; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000097:blood / Q000652:urine; D004123:Dimethylamines / Q000097:blood; D015237:Dinoprost / Q000031:analogs & derivatives / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D013006:Growth Hormone / Q000627:therapeutic use*; D019382:Human Growth Hormone / Q000172:deficiency; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood / Q000652:urine; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009566:Nitrates / Q000097:blood / Q000652:urine; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000097:blood / Q000652:urine; D013234:Stem Cells / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D015415:Biomarkers; D004123:Dimethylamines; D018972:Insulin-Like Growth Factor Binding Protein 3; D009566:Nitrates; D009573:Nitrites; D042461:Vascular Endothelial Growth Factor A; D019382:Human Growth Hormone; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C034516:dimethylamine; D015237:Dinoprost; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D000581:Amidohydrolases; C059999:dimethylargininase; D006152:Cyclic GMP