title: Leptin-induced cardiomyocyte hypertrophy involves selective caveolae and RhoA/ROCK-dependent p38 MAPK translocation to nuclei.
abstract: OBJECTIVE
  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.
  
  
  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 (MbetaCD) 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 MbetaCD, 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 MbetaCD, C3 exoenzyme, and the Rho kinase inhibitor Y-27632.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON N6A 5C1, Canada.
authors.forename: Asad
authors.initials: A
authors.lastname: Zeidan
authors.forename: Sabzali
authors.initials: S
authors.lastname: Javadov
authors.forename: Subrata
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Morris
authors.initials: M
authors.lastname: Karmazyn
mesh_terms: D000199:Actins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced*; D021941:Caveolae / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D021962:Membrane Microdomains / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000502:physiology*; D020742:rhoA GTP-Binding Protein
chemical_list: D000199:Actins; D020738:Leptin; D002784:Cholesterol; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein