Activated epidermal growth factor receptor (ErbB1) protects the heart against stress-induced injury in mice.
Acute, high-intensity stress induces necrotic lesions in the heart. We found that restraint-and-cold (4 degrees C) exposure (RCE) raises plasma lactate dehydrogenase (LDH), creatine kinase (CK), and transaminase activity in a time-dependent manner, with a peak value 7 h after stimulus cessation. At 24 h, signs of necrotic lesions were observed in paraffin sections stained with hematoxylineosin: focal accumulation of mononuclear cells in subendocardial areas of the left ventricle wall and focal hemorrhage in papillary muscles. In contrast, intermale fighting (IF) did not increase plasma CK activity, although LDH and transaminase activities did increase. In IF, no histological evidence of heart injury was observed. Because IF, but not RCE, increased plasma epidermal growth factor (EGF) concentration by approximately 1,000-fold, we hypothesized that EGF receptor (ErbB1) activation may protect the heart against stress-induced injury. To examine this hypothesis, we injected the ErbB1 tyrosine kinase inhibitor tyrphostin AG-1478 (25 mg/kg ip) immediately before mice were exposed to IF. After 3 h, plasma activities of LDH-1 and CK increased. Plasma enzyme activities were as low in control mice (injected with vehicle alone) as in nonfighting mice. In the last experiment, we injected EGF (0.25 mg/kg ip) 20 min before exposing mice to RCE. After 7 h, plasma LDH-1 and CK activities were significantly lower in these animals than in mice injected with vehicle. The effect required ErbB1 activation, because simultaneous administration of AG-1478 completely abolished the effect of exogenous EGF. We conclude that activated ErbB1, by endogenous or exogenous ligands, may protect the heart against stress-induced injury.
Pareja
Miguel
M
Department of Biochemistry and Molecular Biology, University of Barcelona, Spain.
Sánchez
Olga
O
Lorita
Jordi
J
Soley
Maria
M
Ramírez
Ignasi
I
D000374:Aggression / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal; D003080:Cold Temperature; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists* / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D011799:Quinazolines; D012149:Restraint, Physical; D013312:Stress, Physiological / Q000188:drug therapy / Q000503:physiopathology*; D020032:Tyrphostins / Q000494:pharmacology
D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D066246:ErbB Receptors