Pathophysiological consequences of caveolin-1 ablation

Abstract

In my thesis work I investigated several novel pathophysiological consequences of caveolin-1 ablation in the murine model. Because the heart is composed of ∼40% fibroblasts and endothelial cells, which express caveolin-1, we hypothesized that genetic ablation of caveolin-1 in this organ system would lead to measurable pathological abnormalities. Using a variety of approaches including, cardiac gated magnetic resonance imaging (MRI) and transthoracic echocardiography, we investigated the functional consequences of caveolin-1 ablation in the murine heart, finding that caveolin (Cav)-1 null mice develop a progressive hypertrophic cardiomyopathy. Mechanistically, we found that cardiac myocyte hypertrophy occurred secondary to the activation of the p42/44 MAP kinase pathway in cardiac fibroblasts localized to areas of interstitial/perivascular fibrosis.;Another major portion of my thesis work involved investigating the mechanism behind a previously described phenotype in Cav-1 mice, namely resistance to diet induced obesity. Along these lines, we identified that Cav-1 null mice develop whole-body insulin resistance. These changes were due to an overall decrease in insulin receptor protein levels, specifically in adipose tissue. Additionally, this phenotype could be rescued by the transfection of the full-length caveolin-1 cDNA, but not a mutant caveolin-1 cDNA lacking the caveolin scaffolding domain into Cav-1 null MEFs.;We next hypothesized that decreased insulin signaling, as well as loss of caveolin-1 in adipocytes would lead to hyperactivation of protein kinase A (PKA) and elevated lipolysis. Experimentation along these lines revealed that Cav-1 null mice do indeed show elevations PKA activity, however these mice fail to undergo lipolysis. Investigation of the mechanism behind this phenomenon revealed that caveolin-1 normally functions to couple PKA activity to perilipin phosphorylation. Furthermore, we found that Cav-1 null cells were not able to accumulate lipids to the same extent as wild-type cells, thus indicating that the observed resistance to diet induced obesity most likely results from an inability to store triglycerides.;Additional studies into the phenotype of Cav-1 null mice revealed that these animals exhibit significant hypothermia and respond poorly to food restriction or cold exposure. The mechanism behind this phenotype involves reduced substrate availability due to defective lipolysis.