Activated epidermal growth factor receptor (ErbB1) protects the heart against stress-induced injury in mice

Abstract

Acute, high-intensity stress induces necrotic lesions in the heart. We found that restraint-and-cold (4°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 ∼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.

Liver injury after an aggressive encounter in male mice

“…We previously demonstrated that such a high EGF concentration protects the heart from suffering injury (42). Therefore, we studied next whether EGF has a similar role in the liver.…”

“…In some experiments, mice were either sialoadenectomized or sham-operated (24) 1 wk before isolation. In another experiment, intruder mice received an intraperitoneal injection of the EGF receptor inhibitor tyrphostin AG-1478 (Calbiochem, Merck Eurolab, Granada, Spain) (0.25 mg/kg dissolved in 10% DMSO) 20 min before the experiment (42). In another experimental series, intruder mice received anti-EGF antibodies by either an sc injection of 0.15 ml of rabbit anti-mEGF serum 48 h before the experiment, or an intraperitoneal injection of 0.1 ml of rabbit anti-mEGF serum 2 h before the experiment.…”

“…We directly addressed whether EGF secreted during aggressive encounters in mice protects the heart. We found that the inhibition of EGF receptors with tyrphostin AG-1478 made intruder mice susceptible to suffer heart lesions after an aggressive encounter with a resident mouse (42).…”

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…Studies to date support protection via EGF, while TGF fails to protect against acute myocardial I-R injury (Manukyan et al, 2011), and exogenous HB-EGF has yet to be assessed. Injecting EGF (0.25 mg/kg) 20 min before exposing mice to the stress of restraint-and-cold exposure also reduces myocardial injury markers (Pareja et al, 2003), an effect abolished by AG1478. In isolated mouse hearts exogenous EGF protects against detrimental functional effects of continuous epinephrine stimulation (Lorita et al, 2002), with subsequent work showing EGF induces Tyr-phosphorylation of ErbB1 but not ErbB2, and protects against combined epinephrine/I-R injury (Lorita et al, 2009).…”

Epiregulin and EGFR interactions are involved in pain processing

“…EREG produced a robust and dose-dependent increase in licking behavior that was indistinguishable from that (tyrphostin AG 1478; hereinafter, AG 1478; 10 mg/kg) and 2 clinically available (50 mg/kg gefitinib and 75 mg/kg lapatinib) EGFR tyrosine kinase inhibitors in a battery of algesiometric assays. Doses were chosen based on prior in vivo efficacy against stress-induced necrotic lesions in the heart (AG 1478) and in chemoprevention of lung cancer (gefitinib) or breast cancer (lapatinib) in mice (19)(20)(21). We first confirmed that none of the drugs, delivered systemically and at very high doses (AG 1478, 100 mg/kg; gefitinib, 300 mg/ kg; lapatinib, 300 mg/kg), produced significant ataxia over a 1-hour testing period on the rotarod ( Figure 1A).…”