Hypoxia inducible factor-1 improves the actions of nitric oxide and natriuretic peptides after simulated ischemia-reperfusion.
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.
Luciano
Jason A
JA
Heart and Brain Circulation Laboratory, Department of Physiology and Biophysics, Robert Wood Johnson Medical School, Piscataway, NJ 08854-5635, USA.
Tan
Tao
T
Zhang
Qihang
Q
Huang
Emily
E
Scholz
Peter
P
Weiss
Harvey R
HR
D000818:Animals; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D045265:Natriuretic Peptides / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D011817:Rabbits; D015427:Reperfusion Injury / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D045265:Natriuretic Peptides; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D003676:Deferoxamine