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

Abstract

Cell Cycle 7:16, 2509-2518 15 August 2008]; ©2008 Landes Bioscience 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.

Trypanosoma cruziinfection results in the reduced expression of caveolin-3 in the heart

“…Cav-1 null mice display hyperactivation of ERK in the heart and these mice also display cardiac hypertrophy with normal substrate utilization and expression of genes involved in energy metabolism. 36–38 In addition, Cav-3 null mice display increased expression of phosphorylated ERK and a cardiomyopathic phenotype 22…”

Myocyte membrane and microdomain modifications in diabetes: determinants of ischemic tolerance and cardioprotection

“…Supporting the value of targeting caveolins, insulin-resistance in obese and DM mice is reversed by hepatic overexpression of caveolin-3, which substantially enhances InsR signaling [ 315 ]. Nonetheless, basal glucose metabolism appears largely unaltered in hearts lacking either caveolin-3 [ 288 ] or caveolin-1 [ 316 ], and thus also devoid of caveolae, although skeletal muscle insulin-resistance arises in both models [ 308 , 317 ]. While suggesting distinct caveolin/caveolar control of substrate metabolism in cardiac vs. skeletal muscle, cardiac InsR signaling and insulin-resistance have yet to be detailed in these knockout models.…”

Palmitate Diet-induced Loss of Cardiac Caveolin-3: A Novel Mechanism for Lipid-induced Contractile Dysfunction

“…Consequently, the loss of caveolin-3 in the mouse reduces the number of caveolae in muscle and induces T-tubule abnormalities and produces a phenotype similar to muscular dystrophy [22], [23]. Loss of caveolin-1 or caveolin-3 in the heart induces hypertrophy that leads to dilated cardiomyopathy [24]–[27]. Caveolin-3 potentially also has an important role in cardiac calcium regulation [28], [29].…”