Fujino T, Hasebe N, Fujita M, Takeuchi K, Kawabe J, Tobise K, Higashiyama S, Taniguchi N, Kikuchi K
First Department of Internal Medicine, Asahikawa Medical College, Hokkaido, Japan.
Cardiovasc Res. 1998 May;38(2):365-74. doi: 10.1016/s0008-6363(98)00010-8.
Although heparin-binding epidermal growth factor-like growth factor (HB-EGF) is thought to produce hypertrophy in isolated cardiomyocytes via an autocrine mechanism, the pathophysiological role of HB-EGF, in myocardial hypertrophy in vivo, is not yet known. To investigate the involvement of HB-EGF in cardiac remodeling associated with hypertension in vivo, we assayed the expression of HB-EGF mRNA and protein in the left ventricle (LV) during the development of left ventricular hypertrophy in spontaneously hypertensive rats (SHR).
Prior to sacrifice and assay of HB-EGF and EGF-receptor (EGF-R) mRNA, morphologic and hemodynamic variables were measured in SHR and in age-matched Wistar Kyoto rats (WKY). At 5, 9 and 12 weeks of age, rats were killed, their hearts were removed, and the expression of HB-EGF and EGF-R mRNA and protein were measured. In addition, SHR and WKY were treated with enalapril, atenolol, or both for 4 weeks.
In untreated SHR, double products (i.e. systolic blood pressure (sBP) multiplied by heart rate (HR), an index of mechanical load, peaked at 9 weeks. Expression of HB-EGF mRNA was also observed to peak in these animals at 9 weeks, while expression of EGF-R mRNA increased from 5 to 9 weeks, but remained constant thereafter. In untreated WKY, double products and EGF-R mRNA expression did not change over time, whereas the level of HB-EGF message increased gradually. Antibody to HB-EGF reacted primarily with myocyte membranes in SHR, whereas antibody to EGF-R reacted mainly with interstitial cells in these animals. The angiotensin-converting enzyme inhibitor, enalapril, markedly decreased sBP in SHR, whereas the beta 1-adrenoreceptor antagonist, atenolol, significantly decreased 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 expression of EGF-R mRNA.
The enhanced expression of HB-EGF mRNA and protein in LV of SHR suggest that this growth factor may play an important role during the early development of LV hypertrophy and cardiac fibrosis in SHR. The association between double products and HB-EGF expression suggest that the latter may be induced by increased mechanical load and may contribute, in turn, to cardiac remodeling.
尽管肝素结合表皮生长因子样生长因子（HB-EGF）被认为通过自分泌机制在离体心肌细胞中产生肥大，但HB-EGF在体内心肌肥大中的病理生理作用尚不清楚。为了研究HB-EGF在体内与高血压相关的心脏重塑中的作用，我们检测了自发性高血压大鼠（SHR）左心室肥厚发展过程中左心室（LV）中HB-EGF mRNA和蛋白的表达。
在处死大鼠并检测HB-EGF和表皮生长因子受体（EGF-R）mRNA之前，测量SHR和年龄匹配的Wistar Kyoto大鼠（WKY）的形态学和血流动力学变量。在5、9和12周龄时，处死大鼠，取出心脏，测量HB-EGF和EGF-R mRNA及蛋白的表达。此外，用依那普利、阿替洛尔或两者对SHR和WKY进行4周治疗。
在未治疗的SHR中，双乘积（即收缩压（sBP）乘以心率（HR），机械负荷指标）在9周时达到峰值。在这些动物中，HB-EGF mRNA的表达也在9周时达到峰值，而EGF-R mRNA的表达从5周增加到9周，但此后保持不变。在未治疗的WKY中，双乘积和EGF-R mRNA表达随时间没有变化，而HB-EGF信息水平逐渐增加。HB-EGF抗体主要与SHR中的心肌细胞膜反应，而EGF-R抗体主要与这些动物中的间质细胞反应。血管紧张素转换酶抑制剂依那普利显著降低SHR中的sBP，而β1肾上腺素能受体拮抗剂阿替洛尔显著降低HR。虽然单独使用两者都不影响HB-EGF mRNA的表达，但它们的联合使用显著降低了这些大鼠中HB-EGF mRNA的表达以及双乘积，但对EGF-R mRNA的表达没有影响。
SHR左心室中HB-EGF mRNA和蛋白的表达增强表明，这种生长因子可能在SHR左心室肥厚和心脏纤维化的早期发展中起重要作用。双乘积与HB-EGF表达之间的关联表明，后者可能由机械负荷增加诱导，进而可能导致心脏重塑。
