ENHANCED EXPRESSION OF HEPARIN-BINDING EGF-LIKE GROWTH-FACTOR AND ITSRECEPTOR IN HYPERTROPHIED LEFT-VENTRICLE OF SPONTANEOUSLY HYPERTENSIVE RATS

Objectives: Although heparin-binding epidermal growth factor-like grow th factor (HB-EGF) is thought to produce hypertrophy in isolated cardi omyocytes via an autocrine mechanism, the pathophysiological role of H B-EGF, in myocardial hypertrophy in vivo, is not yet known. To investi gate the involvement of HB-EGF in cardiac remodeling associated with h ypertension in vivo, we assayed the expression of HB-EGF mRNA and prot ein in the left ventricle (LV) during the development of left ventricu lar hypertrophy in spontaneously hypertensive rats (SHR). Methods: Pri or to sacrifice and assay of HB-EGF and EGF-receptor (EGF-R) mRNA, mor phologic and hemodynamic variables were measured in SHR and in age-mat ched Wistar Kyoto rats (WKY). At 5, 9 and 12 weeks of age, rats were k illed, their hearts were removed, and the expression of HB-EGF and EGF -R mRNA and protein were measured. In addition, SHR and WKY were treat ed with enalapril, atenolol, or both for 4 weeks. Results: In untreate d SHR, double products (i.e. systolic blood pressure (sBP) multiplied by heart rate (IIR)), an index of mechanical load, peaked at 9 weeks. Expression of HB-EGF mRNA was also observed to peak in these animals a t 9 weeks, while expression of EGF-R mRNA increased from 5 to 9 weeks, but remained constant thereafter. In untreated WKY, double products a nd EGF-R mRNA expression did not change over time, whereas the level o f HB-EGF message increased gradually. Antibody to HB-EGF reacted prima rily with myocyte membranes in SHR, whereas antibody to EGF-R reacted mainly with interstitial cells in these animals. The angiotensin-conve rting enzyme inhibitor, enalapril, markedly decreased sBP in SHR, wher eas the beta(1)-adrenoreceptor antagonist, atenolol, significantly dec reased HR. While neither alone affected the expression of HB-EGF mRNA, their combination significantly reduced the expression of HB-EGF mRNA , as well as double products, in these rats, but had no effect on expr ession of EGF-R mRNA. Conclusions: The enhanced expression of HB-EGF m RNA and protein in LV of SHR suggest that this growth factor may play an important role during the early development of LV hypertrophy and c ardiac fibrosis in SHR. The association between double products and HB -EGF expression suggest that the latter may be induced by increased me chanical load and may contribute, in turn, to cardiac remodeling. (C) 1998 Elsevier Science B.V. All rights reserved.