hypoxia changes the expression of the epidermal growth factor (egf) system in human hearts and cultured cardiomyocytes缺氧变化的表达表皮生长因子(egf)系统在人类心灵和培养的心肌细胞.pdfVIP

Hypoxia Changes the Expression of the Epidermal Growth Factor (EGF) System in Human Hearts and Cultured Cardiomyocytes 1 1 2 2,3 1 Mathias Munk *, Ashfaque Ahmed Memon , Jens Peter Goetze , Lars Bo Nielsen , Ebba Nexo , Boe Sandahl Sorensen1 1 Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark, 2 Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark, 3 Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark Abstract Background: The epidermal growth factor (EGF) receptors HER2 and HER4 and the ligands HB-EGF and NRG1 are crucial for heart development. The purpose of our study was to investigate the role of the complete EGF system in relation to hypoxia of the heart. Methodology/Principal Findings: We examined the mRNA expression by real time PCR of the 4 receptors and 12 ligands from the EGF-system in paired normoxic and hypoxic biopsies isolated from human hearts during coronary artery bypass operation. Compared to normoxic biopsies, hypoxic samples showed down-regulation of HER2 (P = 0.0005) and NRG1 (both a (P = 0.02) and b (P = 0.03) isoforms). In contrast, HB-EGF (P = 0.0008), NRG2b (P = 0.01) and EGFR (P = 0.02) were up- regulated. As HER2 is essential for heart development and we find its expression reduced under hypoxia we investigated the effect of HER2 inhibition in hypoxic HL-1 cardiomyocytes by treatment with trastuzumab (20 nM). This resulted in inhibition of cardiomyocyte proliferation, but interestingly only in hypoxic cells. Co-treatment of HL-1 cells with HB-EGF (10 nM) but not with NRG-1 (5 ng/ml) rescued the cardiomyocytes from HER2 inhibition. HL-1 cardiomyocytes expo