Stabilization of hypoxia inducible factor rather than modulation of collagen metabolism improves cardiac function after acute myocardial infarction in rats.
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-1alpha and -2alpha 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-2alpha 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.
Philipp
Sebastian
S
Department of Cardiology, West-German Heart Center Essen, University of Duisburg-Essen, Essen, Germany. sebastian.philipp@medizin.uni-essen.de
Jürgensen
Jan Steffen
JS
Fielitz
Jens
J
Bernhardt
Wanja M
WM
Weidemann
Alexander
A
Schiche
Astrid
A
Pilz
Bernhard
B
Dietz
Rainer
R
Regitz-Zagrosek
Vera
V
Eckardt
Kai-Uwe
KU
Willenbrock
Roland
R
D000818:Animals; D001483:Base Sequence; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
D017931:DNA Primers; D004791:Enzyme Inhibitors; D051793:Hypoxia-Inducible Factor 1; D012333:RNA, Messenger; D003094:Collagen; D011393:Procollagen-Proline Dioxygenase