Dottorato in Medicina Molecolare

Lipids play a key role during cardiovascular development both in normal and pathological conditions. However, mechanisms how these lipid metabolic pathways regulate cardiovascular homeostasis remain to be discovered and fully characterized. Recently, we focus our attention on the mevalonate pathway, which is responsible for the biosynthesis of many essential lipid molecules such cholesterol, ubiquinone, dolichols and farnesylated proteins. Mevalonate is the precursor of farnesyl-pyrophosphate, a substrate used by several enzymes to produce the final products of the mevalonate pathways. Block of farnesyl-pyrophosphate biosynthesis by statins causes severe cardiovascular system abnormalities that are lethal for zebrafish embryo development. We recently identified by ENU genetic screen the barolo mutant (bar). Interestingly barolo mutant embryos show a phenotype very similar to those treated with statins. Indeed, barolo are characterized by cranial vascular hemorrhages and heart failure in the context of wild-type body morphology. Specific fluorescence microscopy analyses demonstrate that this phenotype is caused by both endothelial and endocardium regression and apoptosis starting between 48 and 65 hpf. Altogether these data suggest that a specific cell death program is activated as consequence of impaired production of prenylated molecules. Biochemical analysis of lipid extracts of bar embryos suggests an unexpected function of the mevalonate pathway in vertebrate heart and blood vessels morphogenesis. We are currently working to address the role of barolo in lipid metabolism during cardiovascular development.