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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/H130    most recent 00298.2008v2 00298.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kim, S.-J. Articles by Crystal, G. J. PubMed PubMed Citation Articles by Kim, S.-J. Articles by Crystal, G. J.

Chronic treatment with insulin-like growth factor I enhances myocyte contraction by upregulation of Akt-SERCA2a signaling pathway

¹Section of Cardiology and ²Department of Anesthesiology, Advocate Illinois Masonic Medical Center; ³Department of Physiology and Biophysics, University of Illinois, Chicago, Illinois; and ⁴Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey

Submitted 18 March 2008 ; accepted in final form 30 April 2008

Chronic treatment with insulin-like growth factor I (IGF-I) improves contractile function in congestive heart failure and ischemic cardiomyopathy. The present study investigated the effect of chronic treatment with IGF-I on intrinsic myocyte function and the role of the phosphatidylinositol (PI)3-kinase-Akt-sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA)2a signaling cascade in these responses. Myocytes were isolated from 23 adult rats and cultured with and without IGF-I (10^–6 M). After 48 h of treatment, myocyte function was evaluated. IGF-I increased contractile function (percent contraction, 7.7 ± 0.3% vs. 4.5 ± 0.3%; P < 0.01) and accelerated relaxation time (time for 70% relengthening, 81 ± 4 vs. 106 ± 5 ms; P < 0.05) compared with untreated myocytes [control (Con)]. The enhanced function was associated with an increase in Ca²⁺ transients assessed by fura-2 (340/380 nm; IGF-I, 0.42 ± 0.02 vs. Con, 0.25 ± 0.01; P < 0.01). The PI3-kinase inhibitor LY-249002 (10^–9 M) abolished the enhanced function caused by IGF-I. IGF-I increased both Akt and SERCA2a protein levels 2.5- and 4.8-fold, respectively, compared with those of Con (P < 0.01); neither phospholamban nor calsequestrin was affected. To evaluate whether the SERCA2a protein was directly mediated by Akt-SERCA2a signaling, IGF-I-induced changes in the SERCA2a protein were compared in myocytes transfected with adenovirus harboring either constitutively active Akt [multiplicity of infection (MOI), 15] or dominant negative Akt (dnAkt; MOI, 15). The ability of IGF-I to upregulate the SERCA2a protein in myocytes transected with active Akt was absent in dnAkt myocytes. Taken together, our findings indicate that chronic treatment with IGF-I enhances intrinsic myocyte function and that this effect is due to an enhancement in intracellular Ca²⁺ handling, secondary to the activation of the PI3-kinase-Akt-SERCA2a signaling cascade.

myocardial contractility; sarco(endo)plasmic reticulum Ca²⁺-ATPase 2a