Pharmacological stimulation of soluble guanylate cyclase modulates hypoxia-inducible factor-1alpha in rat heart.
Mechanical load and ischemia induce a series of adaptive physiological responses by activating the expression of O(2)-regulated genes, such as hypoxia inducible factor-1alpha (HIF-1alpha). The aim of this study was to explore the interaction between HIF-1alpha and soluble guanylate cyclase (sGC) and its second messenger cGMP in cultured cardiomyocytes exposed to hypoxia and in pressure-overloaded heart. In cultured cardiomyocytes of neonatal rats, either sGC stimulator BAY 41-2272 or cGMP analog 8-bromo-cGMP decreased the hypoxia (1% O(2)/5% CO(2))-induced HIF-1alpha expression, whereas the inhibition of protein kinase G by KT-5823 reversed the effect of BAY 41-2272 on the expression under hypoxic conditions. In pressure-overloaded heart induced by suprarenal aortic constriction (AC) in 7-wk-old male Wistar rats, the administration of BAY 41-2272 (2 mg.kg(-1).day(-1)) for 14 days significantly suppressed the protein expression of HIF-1alpha (P < 0.05), vascular endothelial growth factor (P < 0.01), and the number of capillary vessels (P < 0.01) induced by pressure overload. This study suggests that the pharmacological sGC-cGMP stimulation modulates the HIF-1alpha expression in response to hypoxia or mechanical load in the heart.
Tsuruda
Toshihiro
T
Faculty of Medicine, Department of Internal Medicine, Circulatory and Body Fluid Regulation, University of Miyazaki, Miyazaki, Japan. ttsuruda@med.miyazaki-u.ac.jp
Hatakeyama
Kinta
K
Masuyama
Hiroyuki
H
Sekita
Yoko
Y
Imamura
Takuroh
T
Asada
Yujiro
Y
Kitamura
Kazuo
K
D000818:Animals; D000831:Animals, Newborn; D002227:Carbazoles / Q000494:pharmacology; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D015687:Cell Hypoxia; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism; D006973:Hypertension / Q000150:complications / Q000201:enzymology / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018919:Neovascularization, Physiologic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020257:Ventricular Remodeling
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D002227:Carbazoles; D020536:Enzyme Activators; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C073601:KT 5823; C016276:8-bromocyclic GMP; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP