Pharmacological stimulation of soluble guanylate cyclase modulates hypoxia-inducible factor-1alpha in rat heart.

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.

• Authors: Toshihiro Tsuruda, Kinta Hatakeyama, Hiroyuki Masuyama, Yoko Sekita, Takuroh Imamura, Yujiro Asada, Kazuo Kitamura
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 297 Issue 4 Pg. H1274-80 (Oct 2009) ISSN: 1522-1539 [Electronic] United States
• PMID: 19684186 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
• Carbazoles
• Enzyme Activators
• Hif1a protein, rat
• Hypoxia-Inducible Factor 1, alpha Subunit
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridines
• Receptors, Cytoplasmic and Nuclear
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, rat
• KT 5823
• 8-bromocyclic GMP
• Cyclic GMP-Dependent Protein Kinases
• Guanylate Cyclase
• Soluble Guanylyl Cyclase
• Cyclic GMP

Topics

• Animals
• Animals, Newborn
• Carbazoles (pharmacology)
• Cardiomegaly (enzymology, etiology, physiopathology)
• Cell Hypoxia
• Cells, Cultured
• Cyclic GMP (analogs & derivatives, metabolism, pharmacology)
• Cyclic GMP-Dependent Protein Kinases (antagonists & inhibitors, metabolism)
• Disease Models, Animal
• Down-Regulation
• Enzyme Activation
• Enzyme Activators (pharmacology)
• Guanylate Cyclase (metabolism)
• Hypertension (complications, enzymology, physiopathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Male
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Neovascularization, Physiologic
• Protein Kinase Inhibitors (pharmacology)
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• Rats
• Rats, Wistar
• Receptors, Cytoplasmic and Nuclear (agonists, metabolism)
• Second Messenger Systems (drug effects)
• Soluble Guanylyl Cyclase
• Time Factors
• Vascular Endothelial Growth Factor A (metabolism)
• Ventricular Remodeling