Nucleocytoskeleton-mediated endothelial aging in progeria

Lamin A is a component of the nuclear lamina, a scaffold structure of the nuclear envelope in mammalian cells. Over 500 mutations in LMNA gene were linked to more than 15 diseases. Hutchinson-Gilford progeria syndrome (HGPS) is rooted in specific LMNA gene mutations leading to the formation of a structurally and functionally altered protein termed progerin. HGPS is characterized by severe symptoms resembling features of premature aging, including skin atrophy, alopecia, lipodystrophy, osteolysis, atherosclerosis, hypertension, and heart hypertrophy. Most patients die in their teens due to myocardial infarction. A better understanding of the molecular events leading to this devastating disease may also lead to novel insight into processes occurring during normal aging, such as cardiovascular disease. The aim of this project is to study and unravel the molecular basis for the progerin-mediated cardiovascular aging and to investigate how the aged endothelial cells (the inner lining of blood vessels), contribute to HGPS. A novel mouse model expressing progerin in endothelial cells (Prog-Tg) showed retarded growth, increased collagen depositions in the heart, left ventricular hypertrophy, elevation of hypertrophy markers, and premature death, thus closely resembling the cardiovascular phenotype of HGPS patients. On the molecular level, our data indicate disturbed connections between the nucleus and the surrounding filamentous protein meshwork in progerin expressing endothelial cells and an activation of several intracellular events known to potentiate atherosclerosis development. We hypothesize that progerin expression in endothelial cells induces pro- atherogenic events and accelerates cellular aging, leading to secretion of vasoconstriction substances and aging factors exerting extrinsic effects on other tissues. In this project we intend to unveil molecular mechanisms through which progerin activates pro-atherogenic events and the aging machinery in endothelial cells. We will also investigate how the compromised linkage of the nucleus to the cytoskeleton disrupts the ability of cells to sense and process mechanical forces altering cellular responses such as secretion of pro-atherogenic and aging-associated factors in these mice. To relate the molecular disease mechanism to tissue pathologies, we will also extend the phenotypic analyses of the Prog-Tg mice, focussing on arterial stiffening. Our findings are expected to shed light onto processes occurring during normal aging of the vascular system with emphasis on mechanisms leading to increased clogging of aged arteries. They have the potential to identify novel prevention strategies as well as therapeutical treatments to face the increasing challenges in modern medicine to keep our cardiovascular system juvenile.