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

Jason A. Luciano, Tao Tan, Qihang Zhang, Emily Huang, Peter Scholz, Harvey R. Weiss

Research output: Contribution to journalArticle

12 Scopus citations

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-1α 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-1α protects the functional effects of cyclic GMP thorough maintenance of cyclic GMP protein kinase activity after ischemic-reperfusion.

Original languageEnglish (US)
Pages (from-to)421-428
Number of pages8
JournalCellular Physiology and Biochemistry
Volume21
Issue number5-6
DOIs
StatePublished - 2008

All Science Journal Classification (ASJC) codes

  • Physiology

Keywords

  • Cardiac myocytes
  • Cyclic GMP
  • Cyclic GMP protein kinase
  • Hypoxic Inducible Factor-1
  • Ischemia-reperfusion
  • New Zealand white rabbit

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