Submitted on April 12, 2008
Revised on May 21, 2008
Accepted on June 3, 2008
Substrate Uptake and Metabolism are Preserved in Hypertrophic Caveolin-3 Knockout Hearts
Ayanna S Augustus1, Jonathan Buchanan2, Sankar Addya3, Giuseppe Rengo4, Richard Pestell1, Paolo Fortina1, Walter J. Koch3, Andre Bensadoun5, E. Dale Abel6, and Michael P Lisanti7*
1 Thomas Jefferson University
2 University of Utah
3 Jefferson Medical College
4 Thomas Jefferson University, Philadelphia, PA, USA, 19107. Salvatore Maugeri Foundation - IRCCS, Telese (BN), Italy
5 Cornell University
6 University of Utah School of Medicine
7 Kimmel Cancer Ctr at Thomas Jefferson University
* To whom correspondence should be addressed. E-mail: Michael.Lisanti{at}mail.jci.tju.edu.
Caveolin-3 (Cav3), the primary protein component of caveolae in muscle cells, regulates numerous signaling pathways including insulin receptor signaling, and facilitates free fatty acid (FA) uptake by interacting with several fatty acid transport proteins. We previously reported that Cav3 knockout mice (Cav3ko) develop cardiac hypertrophy with diminished contractile function, however, the effects of Cav3 gene ablation on cardiac substrate utilization are unknown. The present study revealed that uptake and oxidation of fatty acids and glucose were normal in hypertrophic Cav3ko hearts. Real-time PCR analysis revealed normal expression of lipid metabolism genes including fatty acid translocase (CD36) and carnitine palmitoyl transferase (CPT-1) in Cav3ko hearts. Interestingly, myocardial cAMP content was significantly increased by 42%, however, this had no affect on PKA activity in Cav3ko hearts. Microarray expression analysis revealed a marked increase in the expression of genes involved in receptor trafficking to the plasma membrane, including Rab4a and the expression of WD repeat/FYVE domain containing proteins. We observed a 4-fold increase in the expression of cellular retinol binding protein-III and 3.5-fold increase in 17
-hydroxysteroid dehydrogenase type11 (17-HSD11), a member of the short-chain dehydrogenase/reductase family involved in the biosynthesis and inactivation of steroid hormones. In summary, loss of Cav3 in the heart leads to cardiac hypertrophy with normal substrate utilization. Moreover, loss of Cav3 mRNA altered the expression of several genes not previously linked to cardiac growth and function.
