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Am J Physiol Heart Circ Physiol 297: H1274-H1280, 2009. First published August 14, 2009; doi:10.1152/ajpheart.00503.2009
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Pharmacological stimulation of soluble guanylate cyclase modulates hypoxia-inducible factor-1{alpha} in rat heart

Toshihiro Tsuruda,1 Kinta Hatakeyama,2 Hiroyuki Masuyama,1 Yoko Sekita,1 Takuroh Imamura,1 Yujiro Asada,2 and Kazuo Kitamura1

1Faculty of Medicine, Department of Internal Medicine, Circulatory and Body Fluid Regulation, and 2Department of Pathology, University of Miyazaki, Miyazaki, Japan

Submitted June 3, 2009 ; accepted in final form August 13, 2009

Mechanical load and ischemia induce a series of adaptive physiological responses by activating the expression of O2-regulated genes, such as hypoxia inducible factor-1{alpha} (HIF-1{alpha}). The aim of this study was to explore the interaction between HIF-1{alpha} 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% O2/5% CO2)-induced HIF-1{alpha} 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-1{alpha} (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-1{alpha} expression in response to hypoxia or mechanical load in the heart.

cyclic guanosine monophosphate; hypoxia; mechanical load; angiogenesis; inflammation


Address for reprint requests and other correspondence: T. Tsuruda, Dept. of Internal Medicine, Circulatory and Body Fluid Regulation, Faculty of Medicine, Univ. of Miyazaki, 5200 Kihara Kiyotake, Miyazaki 889-1692, Japan (e-mail: ttsuruda{at}med.miyazaki-u.ac.jp).






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