ErbB receptors protect the perfused heart against injury induced by epinephrine combined with low-flow ischemia.
ErbB receptor tyrosine kinases are important in maintaining the long-term structural integrity of the heart and in the induction of hypertrophy. In addition, in vivo activation of ErbB1 by epidermal growth factor (EGF) protects the heart against acute stress-induced damage. We examined here whether the ErbB sytem acutely protects the isolated heart in which stress was induced in vitro by ischemia combined with epinephrine infusion (EPI). In perfused mouse hearts, EGF induced Tyr-phosphorylation of ErbB1 but not ErbB2. Neuregulin-1beta (NRG-1beta) induced Tyr-phosphorylation of both ErbB4 and ErbB2. We also found differences in the signaling cascades activated by each growth factor. To stress the perfused mouse heart, we combined EPI with low-flow ischemia. This resulted in (i) loss of left ventricle contraction force ( + dP/dt(max)) and developed pressure (LVDP) after a short period of hypercontractility, (ii) enhanced anaerobic metabolism (lactate production), and (iii) myocyte injury (lactate dehydrogenase (LDH) release). EGF and NRG-1beta had different effects on stressed-heart contractility. EGF reduced to a half the loss of both + dP/dt(max) and LVDP. In contrast, NRG-1beta exacerbated the hypercontractility soon after reperfusion. This is coincident with a transient increase in coronary flow after reperfusion. In spite of these differences in contraction, both EGF and NRG-1beta induced similar early protection as shown by the reduction of LDH release. Our results show that the ErbB system protects the perfused heart against damage induced by acute stress. They reinforce the relevance of ErbB receptors and ligands in cardiac physiology.
Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
Jordi
J
Lorita
Genis
G
Camprecios
Maria
M
Soley
Ignasi
I
Ramirez
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D004837:Epinephrine / Q000494:pharmacology*; D066246:ErbB Receptors / Q000502:physiology*; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008954:Models, Biological; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D020890:Neuregulin-1 / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D066247:Receptor, ErbB-4
D000316:Adrenergic alpha-Agonists; D004837:Epinephrine; D066246:ErbB Receptors; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; C524056:Erbb2 protein, mouse; C587690:Erbb4 protein, mouse