Endothelial dysfunction in a mouse model of human neutral lipid storage disease

Background Systemic knockout of adipose triglyceride lipase (ATGL), the rate-limiting enzyme of triglyceride catabolism, results in a murine phenotype characterized by progressive accumulation of lipids in the heart finally leading to lethal cardiac dysfunction. Since cardiac and vascular dysfunction are closely related we investigated endothelium-dependent and -independent vessel function of ATGL knockout (ATGL(-/-)) mice. Using mice with cardiomyocyterestricted overexpression of ATGL (cardiac-rescued phenotype; ATGL(-/-)/MHC-A35) we were able to differentiate between heart-related and -unrelated effects. Results Aortic relaxation studies and Langendorff perfusion experiments of isolated hearts demonstrated that ATGL (-/-) mice suffer from pronounced microand macrovascular endothelial dysfunction. Experiments with DEA/NO revealed the functional integrity of the smooth muscle cell layer. Since loss in vascular reactivity was restored by ~50 % in cardiac-rescued mice, this phenomenon seems partly a consequence of impaired cardiac contractility. Biochemical analysis revealed that aortic eNOS protein was down-regulated by more than 60% in aortas of ATGL (-/-) mice. As consequence, phosphorylation of VASP at Ser 239 was almost abolished. Both parameters were