Cardioprotective effect of VEGF and venom VEGF-like protein in acute myocardial ischemia in mice: effect on mitochondrial function.
Coronary endothelial dysfunction is involved in cardiac ischemia-reperfusion (IR) injury. Vascular endothelial growth factor (VEGF) activates endothelial cells and exerts cardioprotective effects in isolated hearts. The recently discovered viper venom protein called increasing capillary permeability protein (ICPP) exerts VEGF-like effects in endothelial cells. We examined whether VEGF or ICPP can influence IR outcome in vivo in mice. Dosages of VEGF and ICPP were determined by preliminary blood pressure study. In IR, both the proteins administered intravenously at reperfusion reduced infarct size (IS) by 57% for VEGF and 52% for ICPP (P < 0.01). Pretreatment with a selective VEGFR2 receptor antagonist abolished the reduction in IS. VEGF and ICPP induced ERK phosphorylation in the myocardium. IR triggered mitochondrial pore opening and impaired mitochondrial respiratory function. These effects of IR were prevented by VEGF or ICPP, which increased mitochondrial calcium retention capacity by 37% compared with saline (P < 0.05) and improved mitochondrial respiratory function (by 71% and 65%, respectively for state 3, and 51% and 38% for state 4, P < 0.01 for VEGF). Thus, intravenous administration of VEGF or ICPP at reperfusion largely reduces IS in IR, through stimulation of VEGFR2 receptors. This effect is mediated, at least in part, by improvement of IR-induced mitochondrial dysfunction.
*INSERM U872, Centre de Recherche des Cordeliers, Paris, France; Université Paris-Descartes; Université Pierre and Marie Curie, Paris, France; ‡Institut Pasteur de Tunis, Laboratoire des venins et biomolécules thérapeutiques, Tunis, Tunisia; §Université Tunis El Manar, Tunis, Tunisia; ¶Institut Pasteur de Tunis, Laboratoire d'Epidémiologie moléculaire et Pathologie expérimentale appliquée aux maladies infectieuses LR11IPT04, Tunis, Tunisia; and ‖INSERM U1060-CarMeN, Lyon, France.
Erij
E
Messadi
Zohra
Z
Aloui
Elise
E
Belaidi
Marie-Pascale
MP
Vincent
Elisabeth
E
Couture-Lepetit
Ludovic
L
Waeckel
Johanna
J
Decorps
Nadine
N
Bouby
Ammar
A
Gasmi
Habib
H
Karoui
Michel
M
Ovize
François
F
Alhenc-Gelas
Christine
C
Richer
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000473:pathology; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D011506:Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014757:Viper Venoms / Q000737:chemistry*
D002316:Cardiotonic Agents; D011506:Proteins; D042461:Vascular Endothelial Growth Factor A; D014757:Viper Venoms; D040301:Vascular Endothelial Growth Factor Receptor-2; D002118:Calcium