© 2006 European Society of Cardiology
Stabilization of hypoxia inducible factor rather than modulation of collagen metabolism improves cardiac function after acute myocardial infarction in rats
a Department of Cardiology, West-German Heart Center Essen, University of Duisburg-Essen Essen, Germany
b Department of Cardiology, Charité Hospital und Helios Kliniken Berlin-Buch, Humboldt University Berlin Germany
c Division of Nephrology and Hypertension, Friedrich Alexander University Erlangen Nuernberg Erlangen, Germany
d Department of cardiovascular diseases in women, Charité, and German Heart Institute Berlin Germany
e St. Elisabeth Hospital Halle, Germany
* Corresponding author. Department of Cardiology, West-German Heart Center Essen, University of Duisburg-Essen Hufelandstraße 55, 45122 Essen, Germany. Tel.: +49 201 723 4857. E-mail address: sebastian.philipp{at}medizin.uni-essen.de
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Abstract |
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Prolyl hydroxylase domain-containing enzymes (PHD) hydroxylate a proline residue that controls the degradation of hypoxia inducible factor (HIF). Hypoxia inhibits this hydroxylation thus increasing HIF levels. HIF is upregulated in ischemic tissues, growing tumors and in nonischemic, mechanically stressed myocardium. Pharmacological inhibition of prolyl 4-hydroxylase (P4-H) stabilizes HIF-protein in vitro and may modulate collagen turnover. The aims of this study were to investigate whether inhibition of P4-H protects myocardium against ischemia, and whether the observed effects are related to modulation of collagen metabolism or due to the stabilization of HIF.
Methods: Rats were treated with a specific P4-H inhibitor (P4-HI) or vehicle starting 2 days before induction of myocardial infarction (MI). Rats were investigated 7 or 30 days after MI. Induction of HIF-1
and -2 was visualized by immunohistochemistry. Expression of growth factors (connective tissue growth factor, Osteopontin) and mRNA expression and protein levels of Collagen I and III as well as HIF-2 were measured.
Results: P4-HI augments HIF in the myocardium as early as 24 h after treatment. P4-HI did not alter the MI-induced enhanced expression of growth factors and collagen. Treatment with P4-HI significantly reduced heart and lung weight, improved left ventricular contractility, prevented left ventricular enlargement and improved left ventricular ejection fraction without affecting infarct size after 30 days.
Conclusions: Specific inhibition of the P4-H improved cardiac function without affecting the infarct size after experimental myocardial infarction in rats. Stabilization of HIF rather than inhibition of collagen maturation by P4-HI may prevent cardiac remodeling after MI.
Key Words: Heart failure • Hypoxia inducible factor (HIF) • Infarction • Ischemia • Remodeling
Received February 19, 2005; Revised July 23, 2005; Accepted October 13, 2005
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