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Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 19, 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

Asad Zeidan, Sabzali Javadov, Subrata Chakrabarti and Morris Karmazyn

Department of Physiology and Pharmacology (AZ, SJ, MK) and Pathology (SC), University of Western Ontario, London, ON, Canada

Address correspondence to: Dr. Morris Karmazyn, Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, N6A 5C1, Canada. Tel. 519 661-3872, Fax. 519 661-3827, E-mail: morris.karmazyn{at}schulich.uwo.ca

Aims: Leptin-induced cardiomyocyte hypertrophy is dependent on both RhoA and p38 mitogen activated protein kinases (p38 MAPK) activation. The present study investigated the role of lipid raft/caveolae in these responses and to assess the nature of p38 MAPK activation in mediating leptin-induced hypertrophy.

Methods: Studies were done 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.

Results: Leptin (3.1 nmol/L) treatment for 24h 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 extracellular signal-regulated kinase (ERK1/2) translocation to nuclei which was inhibited by MßCD, C3 exoenzyme and the Rho kinase inhibitor Y27632.

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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