Journal article

Publication year: 2007

Pages: 118-128

Journal: Cardiovascular Research

Volume number: 75

Issue number: 1

ISSN: 0008-6363

eISSN: 1755-3245

DOI Link: https://doi.org/10.1016/j.cardiores.2007.03.003

Publisher: Oxford University Press

Abstract: 

Objective: alpha(2)-macroglobulin (alpha M-2) is an acute phase protein released to the serum upon challenges such as cardiac hypertrophy and infarction. Here we report on the role of alpha M-2 in the induction of hypertrophic cell growth, contractile responsiveness of rat ventricular cardiomyocytes, and on the underlying extracellular regulated kinase 1,2 (ERK1,2) and phosphoinositide 3-kinase (PI3-kinase)/Akt pathways.

Methods: Cell volume and cross-sectional areas were assessed as parameters of hypertrophic growth, and real time RT-PCR for the analysis of hypertrophy-related genes was performed. Protein synthesis was analyzed by C-14-phenylalanine incorporation. Activation of ERK1,2, PI3-kinase and Akt was assessed by immunohistochemical analysis of phosphorylated proteins. Contractile responsiveness was investigated by determination of cell shortening following electrical field stimulation. Intracellular calcium concentration [Ca2+](i) was determined by fluo-3 microfluorometry.

Results: Treatment of ventricular cardiomyocytes for 24 h with alpha M-2 significantly increased cell volume and protein synthesis as well as expression of hypertrophy-associated genes [brain natriuretic protein (BNP), beta-myosin heavy chain (beta-MHC), myosin light chain-2 (MLC-2), atrial natriuretic factor (ANF), and skeletal alpha-actin]. Comparable effects were achieved by treatment of cells with an antibody directed against the alpha M-2-receptor LDL receptor-related protein-1 (LRP-1) and counteracted upon coincubation with receptor-associated protein (RAP), suggesting an involvement of alpha M-2-LRP-1 signalling. Furthermore, alpha M-2 treatment increased sarcoplasmic reticulum Ca2+-ATPase (SERCA-2a) expression, diastolic and systolic [Ca2+](i), and contractile responsiveness after electrical stimulation. Shortly after alpha M-2 stimulation, activation of ERK1,2, Akt, and PI3-kinase pathways was observed. Consequently, alpha N-2-induced protein synthesis was inhibited upon treatment with the ERK1,2 inhibitor UO126 as well as by LY294002 and wortmannin, which inhibit PI3-kinase, and by rapamycin, which inhibits mammalian target of rapamycin (mTOR) downstream of Akt.

Conclusions: Our data show that UN induces hypertrophic cell growth in rat ventricular cardiomyocytes via ERK1,2 and PI3-kinase/Akt and improves cardiac cell function. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Harvard Citation style: Padmasekar, M., Nandigama, R., Wartenberg, M., Schlueter, K. and Sauer, H. (2007) The acute phase protein α₂-macroglobulin induces rat ventricular cardiomyocyte hypertrophy via ERK1,2 and PI3-kinase/Akt pathways, Cardiovascular Research, 75(1), pp. 118-128. https://doi.org/10.1016/j.cardiores.2007.03.003

APA Citation style: Padmasekar, M., Nandigama, R., Wartenberg, M., Schlueter, K., & Sauer, H. (2007). The acute phase protein α₂-macroglobulin induces rat ventricular cardiomyocyte hypertrophy via ERK1,2 and PI3-kinase/Akt pathways. Cardiovascular Research. 75(1), 118-128. https://doi.org/10.1016/j.cardiores.2007.03.003