title: Hearts lacking caveolin-1 develop hypertrophy with normal cardiac substrate metabolism.
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 Ca(2+)-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.
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors: Ayanna S
authors: AS
authors: Augustus
authors: Jonathan
authors: J
authors: Buchanan
authors: Ellen
authors: E
authors: Gutman
authors: Giuseppe
authors: G
authors: Rengo
authors: Richard G
authors: RG
authors: Pestell
authors: Paolo
authors: P
authors: Fortina
authors: Walter J
authors: WJ
authors: Koch
authors: Andre
authors: A
authors: Bensadoun
authors: E Dale
authors: ED
authors: Abel
authors: Michael P
authors: MP
authors: Lisanti
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics*; D000242:Cyclic AMP / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D051242:Caveolin 1; D000242:Cyclic AMP; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018631:ras Proteins; C506947:Atp2a2 protein, mouse; D005947:Glucose