Insulin-like growth factor-II delays myocardial infarction in experimental coronary artery occlusion.
OBJECTIVE
We have previously shown that short pulses of myocardial ischemia cause increased mRNA expression of the insulin-like growth factor II (IGF-II) gene. The expression of IGF-II precedes the expression of its binding protein 5 (IGFBP-5). The cardioprotective actions of the IGF-II peptide and of its binding protein 5 as well as the underlying mechanisms were investigated in this study.


RESULTS
Human recombinant IGF-II (0.25 microgram/ml) was applied by means of direct intramyocardial infusion (IM) for 60 min prior to a 60 min LAD occlusion and 120 min reperfusion. Myocardial infarction, compared to the region at risk, was significantly decreased by IGF-II treatment, whereas infusion of Krebs-Henseleit buffer did not show any protective effect (IGF-II, 78.75 +/- 1.51%; control, 100%; P < 0.005). A comparable degree of cardioprotection was observed after infusion of an equipotent concentration of recombinant human insulin (0.02 IU/ml; 88.25 +/- 1.45%; P < 0.05). Lavendustin A (100 microM), an inhibitor of protein tyrosine kinases, prevented the observed cardioprotection. The protective effect of IGF-II was lost when IGFBP-5 was simultaneously infused.


CONCLUSIONS
IGF-II, a peptide that binds to the insulin receptor and whose mRNA is rapidly transcribed by cardiac myocytes following ischemic stress, is cardioprotective and mimics ischemic preconditioning. Its observed actions are probably based on its metabolic effects and are mediated by the insulin or the IGF-I receptor. IGFBP-5, whose expression follows IGF-II's expression with a short delay, inhibits the cardioprotection afforded by IGF-II and may thus account for the limited temporal duration of ischemic preconditioning.
Vogt
A M
AM
Max Planck Institute for Physiological and Clinical Research, (W.G. Kerckhoff Institute), Department of Experimental Cardiology, Bad Nauheim, Germany.
Htun
P
P
Kluge
A
A
Zimmermann
R
R
Schaper
W
W
D000818:Animals; D003327:Coronary Disease / Q000378:metabolism*; D007328:Insulin / Q000627:therapeutic use; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000627:therapeutic use*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000517:prevention & control*; D010636:Phenols / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000627:therapeutic use; D013552:Swine
D007328:Insulin; D018975:Insulin-Like Growth Factor Binding Protein 5; D010636:Phenols; D011994:Recombinant Proteins; C062898:lavendustin A; D007335:Insulin-Like Growth Factor II; D011505:Protein-Tyrosine Kinases