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

Tsuruda T, Hatakeyama K, Masuyama H, Sekita Y, Imamura T, Asada Y, Kitamura K. Pharmacological stimulation of soluble guanylate cyclase modulates hypoxia-inducible factor-1 alpha in rat heart. Am J Physiol Heart Circ Physiol 297: H1274-H1280, 2009. First published August 14, 2009; doi: 10.1152/ajpheart.00503.2009.-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-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% O-2/5% 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.