Hypoxia inducible factor-1 improves the actions of nitric oxide and natriuretic peptides after simulated ischemia-reperfusion.

Abstract

Ischemia-reperfusion reduces the negative functional effects of cyclic GMP in cardiac myocytes. In this study, we tested the hypothesis that upregulation of hypoxic inducible factor-1 (HIF-1) would improve the actions of cyclic GMP signaling following simulated ischemia-reperfusion. HIF-1 alpha was increased with deferoxamine (150 mg/kg for 2 days). Rabbit cardiac myocytes were subjected to simulated ischemia [15 min 95% N(2)-5% CO(2)] and reperfusion [reoxygenation] to produce myocyte stunning. Cell function was measured utilizing a video-edge detector. Shortening was examined at baseline and after brain natriuretic peptide (BNP, 10(-8), 10(-7)M) or S-nitroso-N-acetyl-penicillamine (SNAP, 10(-6), 10(-5)M) followed by KT5823 (cyclic GMP protein kinase inhibitor, 10(-6)M). Kinase activity was measured via a protein phosphorylation assay. Under control conditions, BNP (-30%) and SNAP (-41%) reduced percent shortening, while KT5823 partially restored function (+18%). Deferoxamine treated control myocytes responded similarly. In stunned myocytes, BNP (-21%) and SNAP (-25%) reduced shortening less and KT5823 did not increase function (+2%). Deferoxamine increased the effects of BNP (-38%) and SNAP (-41%) in stunning and restored the effects of KT5823 (+12%). The cyclic GMP protein kinase increased phosphorylation of several proteins in control HIF-1 +/- cells. Phosphorylation was reduced in stunned cells and was restored in deferoxamine treated stunned cells. This study demonstrated that simulated ischemia-reperfusion reduced the negative functional effects of increasing cyclic GMP and this was related to reduced effects of the cyclic GMP protein kinase. Increased HIF-1 alpha protects the functional effects of cyclic GMP thorough maintenance of cyclic GMP protein kinase activity after ischemic-reperfusion.

• Authors: Jason A Luciano, Tao Tan, Qihang Zhang, Emily Huang, Peter Scholz, Harvey R Weiss
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 21 Issue 5-6 Pg. 421-8 ( 2008) ISSN: 1421-9778 [Electronic] Germany
• PMID: 18453749 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: (c) 2008 S. Karger AG, Basel.

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Natriuretic Peptides
• Nitric Oxide
• Cyclic GMP-Dependent Protein Kinases
• Deferoxamine

Topics

• Animals
• Cyclic GMP-Dependent Protein Kinases (metabolism)
• Deferoxamine (pharmacology)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Muscle Cells (drug effects, metabolism)
• Natriuretic Peptides (metabolism)
• Nitric Oxide (metabolism)
• Rabbits
• Reperfusion Injury (metabolism)