The acute phase protein a2-macroglobulin (a-2M) is synthesized in the liver and released to the serum upon challenges such as cardiac hypertrophy and infarction. Here we report on the role of a-2M in the induction of hypertrophic cell growth, contractile responsiveness of rat ventricular cardiomyocytes as well as on the underlying ERK1,2 and AKT/PI3kinase pathways. Treatment of ventricular cardiomyocytes for 24 h with a-2M significantly increased cell volume, cross-sectional area and protein synthesis as well as expression of hypertrophy-associated genes (c-fos, BNP, beta MHC, ANF, and skeletal a-actin). Within minutes after a-2M stimulation, activation of ERK1,2, Akt as well as PI3-kinase was observed. Consequently, inhibition of ERK1,2, Akt and PI3-kinase pathways by UO126, rapamycin and LY294002/wortmannin, respectively, abolished the hypertrophic response. a-2M treatment increased SERCA2a expression and base line calcium levels as well as amplitudes of electrically evoked calcium spikes. Furthermore, a-2M increased the contractile responsiveness of ventricular cardiomyocytes. In summary our data show that a-2M induces hypertrophic cell growth in rat ventricular cardiomyocytes and improves cardiac cell function.