title: Growth differentiation factor (GDF)-15 blocks norepinephrine-induced myocardial hypertrophy via a novel pathway involving inhibition of epidermal growth factor receptor transactivation.
abstract: Accumulating evidence suggests that growth differentiation factor 15 (GDF-15) is associated with the severity and prognosis of various cardiovascular diseases. However, the effect of GDF-15 on the regulation of cardiac remodeling is still poorly understood. In this present study, we demonstrate that GDF-15 blocks norepinephrine (NE)-induced myocardial hypertrophy through a novel pathway involving inhibition of EGFR transactivation. Both in vivo and in vitro assay indicate that NE was able to stimulate the synthesis of GDF-15. The up-regulation of GDF-15 feedback inhibits NE-induced myocardial hypertrophy, including quantitation of [(3)H]leucine incorporation, protein/DNA ratio, cell surface area, and ANP mRNA level. Further research shows that GDF-15 could inhibit the phosphorylation of EGF receptor and downstream kinases (AKT and ERK1/2) induced by NE. Clinical research also shows that serum GDF-15 levels in hypertensive patients were significant higher than in healthy volunteers and were positively correlated with the thickness of the posterior wall of the left ventricle, interventricular septum, and left ventricular mass, as well as the serum level of norepinephrine. In conclusion, NE induces myocardial hypertrophy and up-regulates GDF-15, and this up-regulation of GDF-15 negatively regulates NE-induced myocardial hypertrophy by inhibiting EGF receptor transactivation following NE stimulation.
authors.affiliation: From the Department of Cardiology, Peking University Third Hospital and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovasicular Receptors Research, Beijing 100191, China.
authors.forename: Xin-ye
authors.initials: XY
authors.lastname: Xu
authors.forename: Ying
authors.initials: Y
authors.lastname: Nie
authors.forename: Fang-fang
authors.initials: FF
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Bai
authors.forename: Zhi-zhen
authors.initials: ZZ
authors.lastname: Lv
authors.forename: You-yi
authors.initials: YY
authors.lastname: Zhang
authors.forename: Zi-jian
authors.initials: ZJ
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000009:adverse effects*; D006332:Cardiomegaly / Q000097:blood* / Q000139:chemically induced / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000097:blood*; D006801:Humans; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000008:administration & dosage / Q000009:adverse effects*; D012189:Retrospective Studies; D015533:Transcriptional Activation / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000316:Adrenergic alpha-Agonists; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C512478:EGFR protein, human; D066246:ErbB Receptors; D009638:Norepinephrine
keywords: Cardiac Hypertrophy; Cell Signaling; Epidermal Growth Factor Receptor (EGFR); Growth Differentiation Factor 15; Growth Factors; Hypertension; Norepinephrine; Transactivation