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

Abstract

. Pharmacological stimulation of soluble guanylate cyclase modulates hypoxia-inducible factor-1␣ 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␣ (HIF-1␣). The aim of this study was to explore the interaction between HIF-1␣ 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-1␣ 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 ⅐ kg Ϫ1 ⅐ day Ϫ1 ) for 14 days significantly suppressed the protein expression of HIF-1␣ (P Ͻ 0.05), vascular endothelial growth factor (P Ͻ 0.01), and the number of capillary vessels (P Ͻ 0.01) induced by pressure overload. This study suggests that the pharmacological sGC-cGMP stimulation modulates the HIF-1␣ expression in response to hypoxia or mechanical load in the heart. cyclic guanosine monophosphate; hypoxia; mechanical load; angiogenesis; inflammation THE MYOCARDIUM IS AN elastic network of cardiomyocytes enmeshed in a collagen matrix that connects the myocytes and supporting intramyocardial coronary vasculature. Mechanical load or ischemia induces a series of adaptive physiological responses in the heart [cardiomyocyte hypertrophy, interstitial fibrosis, and angiogenesis (24, 29)]. Hypoxia inducible factor-1 (HIF-1) is one of the most important transcription factors, composed of following subunits: a constitutively expressed HIF-1␤ and HIF-1␣ induced by hypoxia, and the latter subunit induces the expression of a number of downstream genes, including that for the vascular endothelial growth factor (VEGF) (26). Expressions of HIF-1␣ and VEGF are reported to be activated in hypertrophied and failing heart (17,26,29,30), and the increased number of capillary vessels penetrating the interstitial spaces contribute to supply oxygen and nutrients to the cardiocytes for maintaining the structure and function of pressure-overloaded heart (29, 34).Guanylate cyclase is an enzyme that converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP). Soluble guanylate cyclase (sGC) activated by nitric oxide has been shown to attenuate cardiovascular remodeling by elevating intracellular cGMP levels (6, 18). We and others have previously reported that the pharmacological stimulation of sGC with BAY 41-2272 attenuated the adverse remodeling associated with systemic or pulmonary hypertension, suggesting that sGC-cGMP activation would be one of the impor...

Hemoglobin and Clinical Outcomes in the Vericiguat Global Study in Patients With Heart Failure and Reduced Ejection Fraction (VICTORIA)

“…Given that sGC modulation and hypoxia-inducible factor may both modulate hemoglobin concentrations, this has become a focus of new therapies for patients with renal disease. [14][15][16] Finally, it is possible that vericiguat plays a role in red blood cell senescence, 16,17 resulting in a small decline in circulating red blood cells (without affecting other blood lines) and leading to no effect on the clinical outcomes by simple clearance of aged red blood cells. Some strengths and limitations warrant consideration.…”

Inhibition of hypoxia-inducible factor 1α accumulation by glyceryl trinitrate and cyclic guanosine monophosphate

“…These results are in agreement with previous studies [30][31][32] showing that NO via cGMP production prevents hypoxia-mediated acquisition of malignant phenotypes in tumour cells and suggest that modulation of HIF-1α may be an important aspect of the mechanism by which NO/cGMP signalling regulates hypoxic responses. Although many of the studies examining the regulatory effects of NO on HIF-1α accumulation and/or HIF-1 activity have proposed cGMP-independent mechanisms of HIF-1 regulation, Tsuruda et al [37] have found that activation of sGC/cGMP signalling in cultured cardiomyocytes decreased hypoxia-induced HIF-1α protein accumulation; this further supports the notion that the cGMPdependent signalling interferes with hypoxic induction of HIF-1α accumulation and suggests that such mechanism of HIF-1α modulation may apply to a variety of normal and transformed cells.…”