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This Article Full Text Full Text (PDF) Supplemental Table All Versions of this Article: 295/2/H657    most recent 00387.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Augustus, A. S. Articles by Lisanti, M. P. Search for Related Content PubMed PubMed Citation Articles by Augustus, A. S. Articles by Lisanti, M. P.

Substrate uptake and metabolism are preserved in hypertrophic caveolin-3 knockout hearts

¹Department of Cancer Biology and ²Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; ³Dipartimento di Medicina Sperimentale e Patologia, Universita’ degli Studi "La Sapienza," Roma, Italy; ⁴Division of Nutritional Sciences, Cornell University, Ithaca, New York; ⁵Program in Human Molecular Biology and Genetics and Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, Utah; ⁶Muscular and Neurodegenerative Disease Unit, University of Genova; and ⁷G. Gaslini Pediatric Institute, Genova, Italy

Submitted 12 April 2008 ; accepted in final form 3 June 2008

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 FA 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 the uptake and oxidation of FAs and glucose were normal in hypertrophic Cav3KO hearts. Real-time PCR analysis revealed normal expression of lipid metabolism genes including FA translocase (CD36) and carnitine palmitoyl transferase-1 in Cav3KO hearts. Interestingly, myocardial cAMP content was significantly increased by 42%; however, this had no effect 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 fourfold increase in the expression of cellular retinol binding protein-III and a 3.5-fold increase in 17β-hydroxysteroid dehydrogenase type 11, a member of the short-chain dehydrogenase/reductase family involved in the biosynthesis and inactivation of steroid hormones. In summary, a loss of Cav3 in the heart leads to cardiac hypertrophy with normal substrate utilization. Moreover, a loss of Cav3 mRNA altered the expression of several genes not previously linked to cardiac growth and function. Thus we have identified a number of new target genes associated with the pathogenesis of cardiac hypertrophy.

cardiomyopathy; caveolae; fatty acids; isolated perfused hearts; adenosine 3',5'-cyclic monophosphate

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