© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
High glucose induces cardiac insulin-like growth factor I resistance in ventricular myocytes: role of Akt and ERK activation
University of Wyoming College of Health Sciences, P.O. Box 3375, Laramie, WY 82071, USA
* Corresponding author. Tel.: +1-307-766-6120; fax: +1-307-766-2953. jren{at}uwyo.edu
Objective: Cardiac resistance to IGF-1 occurs in diabetes and is attributed to cardiac dysfunction in diabetes. However, the mechanism of action responsible for cardiac IGF-1 resistance is still unknown. This study was designed to examine the impact of high glucose on IGF-1-induced contractile response and activation of serine-threonine kinase Akt as well as extracellular signal-regulated kinase (ERK1/2) in cardiac myocytes. Methods: Isolated adult rat ventricular myocytes were cultured for 12–18 h in a serum-free medium containing either normal (NG, 5.5 mM) or high (HG, 25.5 mM) glucose. Mechanical properties were evaluated using an IonOptix MyoCam® system. Myocytes were electrically stimulated at 0.5 Hz and contractile properties analyzed included peak shortening (PS), time-to-PS (TPS) and time-to-90% relengthening (TR90). Intracellular Ca2+-induced Ca2+ release was measured as fura-2 fluorescence intensity change (
FFI). Protein levels of total and phosphorylated Akt and ERK1/2, indicators of Akt and ERK1/2 activation, IGF-1 receptors (pro-IGF-1R and IGF-1R
) as well as the glucose transporter GLUT4 were assessed by Western blot. Results: IGF-1 (10–10–10–6 M) elicited a dose-dependent increase in PS and FFI in myocytes maintained in NG medium. However, IGF-1 induced a negative response on PS and FFI in HG myocytes. The IGF-1-induced responses in NG or HG myocytes were blunted by the IGF-1 receptor antagonist H-1356. Western blot analysis revealed that IGF-1R but not pro-IGF-1R was reduced in HG myocytes. While IGF-1 (10–6 M) upregulated total Akt protein levels in both NG and HG myocytes, it only induced a significant activation of Akt in NG but not HG myocytes. IGF-1 elicited comparable ERK1/2 activation in both NG and HG myocytes. Conclusion: These results suggest that the cardiac IGF-1 resistance in diabetes is likely attributed, at least in part, to reduced IGF-1R and attenuated IGF-1-induced Akt phosphorylation under elevated extracellular glucose.
KEYWORDS Calcium (cellular); Cell culture/isolation; Contractile function; Growth factors; Myocytes; Protein kinases
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