Stabilization of hypoxia inducible factor rather than modulation of collagen metabolism improves cardiac function after acute myocardial infarction in rats

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• 作者：Sebastian Philipp ; Jan Steffen Jü ; rgensen ; Jens Fielitz ; Wanja M. Bernhardt ; Alexander Weidemann ; Astrid Schiche ; Bernhard Pilz ; Rainer Dietz ; Vera Regitz-Zagrosek ; Kai-Uwe Eckardt and Roland Will
• 关键词：Heart failure ; Hypoxia inducible factor (HIF) ; Infarction ; Ischemia ; Remodeling
• 刊名：European Journal of Heart Failure
• 出版年：2006
• 出版时间：June 2006
• 年：2006
• 卷：8
• 期：4
• 页码：347-354
• 全文大小：282 K

文摘

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-1α and -2α 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-2α 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.