Hearts lacking caveolin-1 develop hypertrophy with normal cardiac substrate metabolism

Ayanna S. Augustus, Jonathan Buchanan, Ellen Gutman, Giuseppe Rengo, Richard G. Pestell, Paolo Fortina, Walter J. Koch, Andre Bensadoun, E. Dale Abel, Michael P. Lisanti

Research output: Contribution to journalArticle

Abstract

Long-chain fatty acids (FA) are the primary energy source utilized by the adult heart. However, during pathological cardiac hypertrophy the fetal gene program is reactivated and glucose becomes the major fuel source metabolized by the heart. Herein we describe the metabolic phenotype associated with caveolin-1(Cav1) gene ablation (Cav1ko) in cardiac fibroblasts. Cav1, the primary protein component of caveolae in non-muscle cells co-localizes with a number of proteins involved in substrate metabolism, including, FA translocase (CD36) and the insulin receptor. We demonstrate that Cav1ko hearts develop cardiac hypertrophy and contractile dysfunction at 5-6mos of age. Surprisingly, we observed an increase in the uptake of Intralipid triglyceride and albumin bound FA by 25% and 47%, respectively, in Cav1ko hearts. Isolated perfused heart studies revealed no significant difference in glucose oxidation and glycolysis, however, we observed a trend toward increased FA oxidation in Cav1ko hearts. Real-time PCR analysis revealed no significant changes in the expression of genes involved in FA and glucose metabolism. We also report myocardial triglyceride, fatty acid and cholesterol levels are significantly reduced in Cav1ko hearts. Microarray gene expression analysis revealed changes in genes that regulate calcium ion and lipid transport as well as a number of genes not previously linked to cardiac hypertrophy. We observed a 4-fold increase in tetraspanin-2 gene expression, a transmembrane protein implicated in regulating intracellular trafficking. Oxysterol binding protein related protein-3, which has been implicated in intracellular lipid synthesis and transport, was increased 3.6-fold. In addition, sarcoplasmic reticulum Ca2+-ATPase 3, and calcyclin gene transcripts were significantly increased in Cav1ko hearts. In summary, targeted loss of Cav1 produces a unique model of cardiac hypertrophy with normal substrate utilization and expression of genes involved in energy metabolism.

Original languageEnglish
Pages (from-to)2509-2518
Number of pages10
JournalCell Cycle
Volume7
Issue number16
Publication statusPublished - Aug 15 2008

Keywords

  • Calcium
  • Cardiomyopathy
  • Caveolae
  • Fatty acids
  • Gene expression profile
  • Glucose
  • Lipoproteins
  • Ras

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

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  • Cite this

    Augustus, A. S., Buchanan, J., Gutman, E., Rengo, G., Pestell, R. G., Fortina, P., Koch, W. J., Bensadoun, A., Abel, E. D., & Lisanti, M. P. (2008). Hearts lacking caveolin-1 develop hypertrophy with normal cardiac substrate metabolism. Cell Cycle, 7(16), 2509-2518.