HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Li, S.-Y. Articles by Ren, J. Search for Related Content PubMed PubMed Citation Articles by Li, S.-Y. Articles by Ren, J.

Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, Wyoming 82071, USA

(Requests for offprints should be addressed to J Ren; Email: jren{at}uwyo.edu)

^* (S-Y Li, C X Fang and N S Aberle II contributed equally to this work)

Insulin-like growth factor-I (IGF-1) ameliorates cardiac dysfunction in diabetes although the mechanism of action remains poorly understood. This study examined the role of PI-3 kinase/Akt/mammalian target of rapamycin (mTOR) and calcineurin pathways in cardiac effects of IGF-1 against glucose toxicity. Adult rat ventricular myocytes were cultured for 8 h with either normal (NG, 5.5 mM) or high (HG, 25.5 mM) glucose, in the presence or absence of IGF-1 (10–500 nM), the PI-3 kinase/Akt inhibitor LY294002 (10 µM), the mTOR inhibitor rapamycin (20 µM) or the calcineurin inhibitors cyclosporin A (5 µM) or FK506 (10 mg/l). Mechanical properties were evaluated using an IonOptix MyoCam system. HG depressed peak shortening (PS), reduced maximal velocity of shortening/relengthening (± dl/dt) and prolongs time-to-90% relengthening (TR₉₀), which were abolished by IGF-1 (100 and 500 nM). Interestingly, the IGF-1-elicited protective effect against HG was nullified by either LY294002 or rapamycin, but not by cyclosporine A or FK506. None of the inhibitors affected cell mechanics. Western blot analysis indicated that HG and IGF-1 stimulated phosphorylation of Akt and mTOR. HG also activated p70s6k and suppressed GSK-3ß phosphorylation. However, the HG-induced alterations in phosphorylation of Akt, mTOR, p70s6k and GSK-3ß were significantly reversed by IGF-1. Protein expression of Akt, mTOR, p70s6k, GSK-3ß, SERCA2a and phospholamban was unaffected by HG, IGF-1 or rapamycin. Rapamycin significantly enhanced Akt phosphorylation whereas it inhibited mTOR phosphorylation. Collectively, our data suggest that IGF-1 may provide cardiac protection against glucose in part through a PI-3 kinase/Akt/mTOR/ p70s6k-dependent and calcineurin-independent pathway.

This article has been cited by other articles:

				E. R. Porrello, J. R. Bell, J. D. Schertzer, C. L. Curl, J. R. McMullen, K. M. Mellor, R. H. Ritchie, G. S. Lynch, S. B. Harrap, W. G. Thomas, et al. Heritable pathologic cardiac hypertrophy in adulthood is preceded by neonatal cardiac growth restriction Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2009; 296(3): R672 - R680. [Abstract] [Full Text] [PDF]

				Q. Li, S. Wu, S.-Y. Li, F. L. Lopez, M. Du, J. Kajstura, P. Anversa, and J. Ren Cardiac-specific overexpression of insulin-like growth factor 1 attenuates aging-associated cardiac diastolic contractile dysfunction and protein damage Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1398 - H1403. [Abstract] [Full Text] [PDF]

				Q. LI and J. REN CARDIAC OVEREXPRESSION OF METALLOTHIONEIN RESCUES CHRONIC ALCOHOL INTAKE-INDUCED CARDIOMYOCYTE DYSFUNCTION: ROLE OF AKT, MAMMALIAN TARGET OF RAPAMYCIN AND RIBOSOMAL P70S6 KINASE Alcohol Alcohol., November 1, 2006; 41(6): 585 - 592. [Abstract] [Full Text] [PDF]

				A. A. Caro and A. I. Cederbaum Role of Phosphatidylinositol 3-Kinase/AKT as a Survival Pathway against CYP2E1-Dependent Toxicity J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 360 - 372. [Abstract] [Full Text] [PDF]