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GW23-e1843
REGULATION OF TRANSFORMING GROWTH FACTOR β1 SIGNALLING IN THE POST-ISCHAEMIC MOUSE HEART
  1. Yuanjing Li1,
  2. Guanglong He2
  1. 1The Department of Cardiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
  2. 2Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, Columbus, OH, USA

    Abstract

    Objectives eNOS-derived NO induces acute phase tissue hyperoxia in vivo and hyperoxia induces fibroblast trans-differentiation in vitro. However, little is known about the effect of reperfusion-induced hyperoxia on myocardial infarct healing. The current study is to determine how late phase reperfusion hyperoxia and NO regulate cardiac myofibroblast formation.

    Methods C57BL/6 wild-type, eNOS−/− and iNOS−/− mice were subjected to 30-min LAD occlusion followed by 14-days of reperfusion. Myocardial tissue PO2 was monitored with electron paramagnetic resonance oximetry. Protein expression of TGF-beta1, p-Smad2/3, t-Smad2/3, p21 and α-SMA were measured with ELISA and western blot.

    Results There was an acute phase overshoot of tissue Po2 in the WT and iNOS−/− but not eNOS−/− mice. After 60 min reperfusion, tissue hyperoxia was observed in all three groups and peaked at day 3 with significantly lower PO2 in the eNOS−/− mice than that in the WT and iNOS−/− mice (22.4±0.8 vs 39.8±1.13 and 26.9±1.3 mm Hg). Protein expression of the total and active TGF-β1, p-Smad2/3 over t-Smad2/3 ratio, p21 and α-SMA were significantly increased after reperfusion in the WT mice. Knockout of eNOS or iNOS further increased the expression of these signals. Immunohistochemical staining indicated the expression of α-SMA in the infarct area. Immunoprecipitation demonstrated the nitration of TGF-β RII. Carbogen (95% O2+5% CO2) treatment increased the expression of p-Smad2/3 over t-Smad2/3 which was inhibited by EUK134 (10006329 EUK 134) and sodium nitroprusside.

    Conclusions Late phase reperfusion tissue hyperoxia promoted while eNOS-/iNOS-derived NO/ONOO inhibited cardiac TGF-β1 signalling and myofibroblast trans-differentiation. These findings may provide new targets to improve myocardial infarct healing and repair.

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