Genistein attenuates hypoxic pulmonary hypertension via enhanced nitric oxide signaling and the erythropoietin system.
Upregulation of the erythropoietin (EPO)/EPO receptor (EPOR) system plays a protective role against chronic hypoxia-induced pulmonary hypertension (hypoxic PH) through enhancement of endothelial nitric oxide (NO)-mediated signaling. Genistein (Gen), a phytoestrogen, is considered to ameliorate NO-mediated signaling. We hypothesized that Gen attenuates and prevents hypoxic PH. In vivo, Sprague-Dawley rats raised in a hypobaric chamber were treated with Gen (60 mkg/kg) for 21 days. Pulmonary hemodynamics and vascular remodeling were ameliorated in Gen-treated hypoxic PH rats. Gen also restored cGMP levels and phosphorylated endothelial NO synthase (p-eNOS) at Ser(1177) and p-Akt at Ser(473) expression in the lungs. Additionally, Gen potentiated plasma EPO concentration and EPOR-positive endothelial cell counts. In experiments with hypoxic PH rats' isolated perfused lungs, Gen caused NO- and phosphatidylinositol 3-kinase (PI3K)/Akt-dependent vasodilation that reversed abnormal vasoconstriction. In vitro, a combination of EPO and Gen increased the p-eNOS and the EPOR expression in human umbilical vein endothelial cells under a hypoxic environment. Moreover, Gen potentiated the hypoxic increase in EPO production from human hepatoma cells. We conclude that Gen may be effective for the prevention of hypoxic PH through the improvement of PI3K/Akt-dependent, NO-mediated signaling in association with enhancement of the EPO/EPOR system.
Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan skuriyam@juntendo.ac.jp.
Sachiko
S
Kuriyama
Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Yoshiteru
Y
Morio
Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Michie
M
Toba
Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Tetsutaro
T
Nagaoka
Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Fumiyuki
F
Takahashi
Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Shin-Ichiro
S
Iwakami
Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Kuniaki
K
Seyama
Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Kazuhisa
K
Takahashi
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D015687:Cell Hypoxia; D006152:Cyclic GMP / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004921:Erythropoietin / Q000096:biosynthesis* / Q000502:physiology; D019833:Genistein / Q000494:pharmacology* / Q000627:therapeutic use; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000517:prevention & control; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014665:Vasodilator Agents / Q000494:pharmacology; D017725:Ventricular Pressure
D000959:Antihypertensive Agents; D014665:Vasodilator Agents; D004921:Erythropoietin; D009569:Nitric Oxide; D019833:Genistein; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D006152:Cyclic GMP
endothelial nitric oxide synthase; erythropoietin; genistein; phosphatidylinositol 3-kinase; pulmonary hypertension