Cardiovascular Research Advance Access first published online on September 19, 2007
This version [Corrected Proof] published online on October 24, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm020
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Leptin-induced cardiomyocyte hypertrophy involves selective caveolae and RhoA/ROCK-dependent p38 MAPK translocation to nuclei
1 Department of Physiology and Pharmacology, University of Western Ontario, London, ON N6A 5C1, Canada
2 Department of Pathology, University of Western Ontario, London, ON N6A 5C1, Canada
* Corresponding author. Tel: +1 519 661 3872; fax: +1 519 661 3827. E-mail address: morris.karmazyn{at}schulich.uwo.ca
Aims: Leptin-induced cardiomyocyte hypertrophy is dependent on both RhoA and p38 mitogen-activated protein kinase (p38 MAPK) activation. The present study investigated the role of lipid raft/caveolae in these responses and assessed the nature of p38 MAPK activation in mediating leptin-induced hypertrophy.
Methods and results: Studies were carried out using cultured neonatal rat ventricular myocytes. Pharmacological, molecular, microscopy, and confocal imaging techniques were used to assess the role of caveolae in leptin-induced hypertrophy and to study the underlying cellular mechanisms. Leptin (3.1 nmol/L) treatment for 24 h significantly increased caveolae number two-fold and increased expression of caveolin-3 to 278 ± 14% of control values. These effects were associated with increased cell surface area by 29 ± 5% and leucine incorporation by 40 ± 6%. The hypertrophic effect of leptin was associated with significant activation of RhoA (422 ± 26%) and a decrease in the G-actin-to-F-actin ratio from 3.1 ± 0.2 to 0.9 ± 0.1. Caveolae disruption with methyl-beta-cyclodextrin (MßCD) potently attenuated leptin-induced cell hypertrophy and the associated signalling. RhoA was detected in caveolae fraction of a sucrose gradient after treatment with leptin for 5 min, indicating subcellular translocation of RhoA: this effect was inhibited by MßCD, the RhoA inhibitor C3 exoenzyme, and by disruption of actin filaments with latrunculin B. Furthermore, leptin-induced hypertrophy was associated with p38 MAPK but not with extracellular signal-regulated kinase (ERK1/2) translocation to nuclei, which was inhibited by MßCD, C3 exoenzyme, and the Rho kinase inhibitor Y-27632.
Conclusion: Our results indicate that p38 import into nuclei represents a key mechanism for leptin-induced hypertrophy acting through lipid raft/caveolae and a RhoA-dependent pathway.
KEYWORDS Cardiomyocytes; Leptin; Hypertrophy; RhoA; Caveolae
Time for primary review 38 days
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Cardiovasc Res 2008 77: 4-5.
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