Premature Vascular Aging with Features of Plaque Vulnerability in an Atheroprone Mouse Model of Hutchinson-Gilford Progeria Syndrome with Ldlr Deficiency.

Hutchinson-Gilford progeria syndrome (HGPS) is among the most devastating of the laminopathies, rare genetic diseases caused by mutations in genes encoding nuclear lamina proteins. HGPS patients age prematurely and die in adolescence, typically of atherosclerosis-associated complications. The mechanisms of HGPS-related atherosclerosis are not fully understood due to the scarcity of patient-derived samples and the availability of only one atheroprone mouse model of the disease. Here, we generated a new atherosusceptible model of HGPS by crossing progeroid Lmna(G609G/G609G) mice, which carry a disease-causing mutation in the Lmna gene, with Ldlr(-/-) mice, a commonly used preclinical atherosclerosis model. Ldlr(-/-)Lmna(G609G/G609G) mice aged prematurely and had reduced body weight and survival. Compared with control mice, Ldlr(-/-)Lmna(G609G/G609G) mouse aortas showed a higher atherosclerosis burden and structural abnormalities typical of HGPS patients, including vascular smooth muscle cell depletion in the media, adventitial thickening, and elastin structure alterations. Atheromas of Ldlr(-/-)Lmna(G609G/G609G) mice had features of unstable plaques, including the presence of erythrocytes and iron deposits and reduced smooth muscle cell and collagen content. Ldlr(-/-)Lmna(G609G/G609G) mice faithfully recapitulate vascular features found in patients and thus provide a new tool for studying the mechanisms of HGPS-related atherosclerosis and for testing therapies.