Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Carbazoles / pharmacology
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Cardiomegaly / enzymology
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Cardiomegaly / etiology
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Cardiomegaly / physiopathology
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Cell Hypoxia
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Cells, Cultured
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Cyclic GMP / analogs & derivatives
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Cyclic GMP / metabolism*
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Cyclic GMP / pharmacology
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Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors
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Cyclic GMP-Dependent Protein Kinases / metabolism
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Disease Models, Animal
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Down-Regulation
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Enzyme Activation
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Enzyme Activators / pharmacology*
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Guanylate Cyclase / metabolism
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Hypertension / complications
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Hypertension / enzymology
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Hypertension / physiopathology
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Male
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Myocytes, Cardiac / drug effects*
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Myocytes, Cardiac / enzymology
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Myocytes, Cardiac / pathology
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Neovascularization, Physiologic
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Protein Kinase Inhibitors / pharmacology
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Pyrazoles / pharmacology*
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Pyridines / pharmacology*
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Rats
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Rats, Wistar
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Second Messenger Systems / drug effects
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Soluble Guanylyl Cyclase
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Time Factors
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Vascular Endothelial Growth Factor A / metabolism
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Ventricular Remodeling
Substances
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3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
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Carbazoles
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Enzyme Activators
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Hif1a protein, rat
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Hypoxia-Inducible Factor 1, alpha Subunit
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Protein Kinase Inhibitors
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Pyrazoles
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Pyridines
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Receptors, Cytoplasmic and Nuclear
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, rat
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KT 5823
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8-bromocyclic GMP
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Cyclic GMP-Dependent Protein Kinases
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Guanylate Cyclase
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Soluble Guanylyl Cyclase
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Cyclic GMP