Role of the Epidermal Growth Factor Receptor in Signaling Strain-dependent Activation of the Brain Natriuretic Peptide Gene

Abstract

The epidermal growth factor receptor (EGFR) and ectoshedding of heparin-binding epidermal growth factor (HBEGF), an EGFR ligand, have been linked to the development of cardiac myocyte hypertrophy. However, the precise role that the liganded EGFR plays in the transcriptional activation of the gene program that accompanies hypertrophy remains undefined. Utilizing the human (h) BNP gene as a model of hypertrophy-dependent gene activation, we show that activation of the EGFR plays an important role in mediating mechanical strain-dependent stimulation of the hBNP promoter. Strain promotes endothelin (ET) generation through NAD(P)H oxidase-dependent production of reactive oxygen species. ET in turn induces metalloproteinase-mediated cleavage of pro-HBEGF and ectoshedding of HBEGF, which activates the EGFR and stimulates hBNP promoter activity. HBEGF also stimulates other phenotypic markers of hypertrophy including protein synthesis and sarcomeric assembly. The antioxidant N-acetylcysteine or the NAD(P)H oxidase inhibitor, apocynin, inhibited strain-dependent activation of the ET-1 promoter, HBEGF shedding, and hBNP promoter activation. The metalloproteinase inhibitor, GM-6001, prevented the induction of HBEGF ectoshedding and the hBNP promoter response to strain, suggesting a critical role for the metalloproteinase-dependent cleavage event in signaling the strain response. These findings suggest that metalloproteinase activity as an essential step in this pathway may prove to be a relevant therapeutic target in the management of cardiac hypertrophy.

Myocardial Mineralocorticoid Receptor Activation by Stretching and Its Functional Consequences

“…19,25,26 EGFR transactivation seems to be performed by metalloproteinase-dependent cleavage of proheparin-binding EGF, which promotes ectoshedding of heparin-binding EGF. 27,28 Heparin-binding EGF is a well-known ligand of EGFR, and binding of heparin-binding EGF to EGFR leads to activation of the receptor by tyrosine autophosphorylation. Once EGFR is phosphorylated, the downstream signals increase mitochondrial O 2˙ production.…”

Cardiomyocyte hypertrophy and degradation of connexin43 through spatially restricted autocrine/paracrine heparin-binding EGF

“…Although proHB-EGF is biologically active as a juxtacrine growth factor that can signal to immediately neighboring cells in a nondiffusible manner (23- 25), several studies have revealed the crucial role of metalloproteases in the enzymatic conversion of proHB-EGF to soluble HB-EGF, which binds to and activates the EGFR. Hypertrophic stimuli such as mechanical strain (26) and G protein-coupled receptors agonists (3) mediate cardiac hypertrophy through the shedding of membrane-bound proHB-EGF. Thus, an autocrine͞paracrine loop, which requires the diffusible, soluble form of HB-EGF, is necessary for subsequent transactivation of the EGFR to produce the hypertrophic response.…”

Interaction and Inhibitory Cross-Talk between Endothelin and ErbB Receptors in the Adult Heart

“…Cross-talk between GPCRs and RTKs has been described in a wide variety of tissues, but interactions of the nature described here between ET A and erbB2/4 have not been reported in any tissue. In studies of neonatal myocytes, ET-1 was shown to transactivate EGF receptors (Asakura et al, 2002;Anderson et al, 2004), whereas another study in the same system showed inhibition of EGF receptor-mediated Akt phosphorylation upon activation of G␣ q (Sabri et al, 2002). In renal mesangial cells, Grewal et al (2001) found that GPCRs desensitize and down-regulate EGF receptors.…”

“…In heart tissue, transactivation of EGFR (erbB1) by ET-1 has been shown to occur in neonatal rat cardiac myocytes (Asakura et al, 2002;Anderson et al, 2004). Much of our current understanding of cross-talk between GPCRs and RTKs is based on work in embryonic/neonatal tissues or immortalized cell lines.…”