Abstract
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 LmnaG609G/G609G mice, which carry a disease-causing mutation in the Lmna gene, with Ldlr−/− mice, a commonly used preclinical atherosclerosis model. Ldlr−/−LmnaG609G/G609G mice aged prematurely and had reduced body weight and survival. Compared with control mice, Ldlr−/−LmnaG609G/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−/−LmnaG609G/G609G mice had features of unstable plaques, including the presence of erythrocytes and iron deposits and reduced smooth muscle cell and collagen content. Ldlr−/−LmnaG609G/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.
Highlights
Lamins are key components of the nuclear envelope that play pivotal roles in maintaining a proper nuclear structure and function
Ldlr−/− LmnaG609G/G609G and heterozygous Ldlr−/− LmnaG609G/+ mice both had a shorter lifespan and lower body weight than control Ldlr−/− Lmna+/+ mice with normal lamin A expression (Figure 1a,b for males; Figure A1a,b for females) and showed an aging phenotype with progressive fat loss closely resembling that of progeric mice without Ldlr deficiency
Hutchinson–Gilford progeria syndrome (HGPS) patients are heterozygous for the LMNA mutation; LmnaG609G mice seem to be more resistant to progerin-induced damage [14], and all further studies were performed with homozygous Ldlr−/− LmnaG609G/G609G mice because their phenotype is more severe and more similar to that seen in human patients
Summary
Lamins are key components of the nuclear envelope that play pivotal roles in maintaining a proper nuclear structure and function. Mutations in genes encoding lamins lead to a variety of diseases collectively termed laminopathies, which affect one or multiple tissues, including muscular, cardiac, adipose, and osseous tissue. One of the more severe laminopathies is Hutchinson–Gilford progeria syndrome (HGPS), which is caused by progerin, an anomalous variant of lamin A. HGPS patients begin to show symptoms characteristic of advanced age, including. Most HGPS patients die from atherosclerosis-related causes, mainly myocardial infarction or stroke, at an average age of 14.6 years [5,6]. Autopsies reveal that apart from atherosclerotic lesions, HGPS arteries have severe structural abnormalities, including excessive calcification, adventitial thickening, smooth muscle cell loss and extracellular matrix accumulation in the media, and elastin structure alterations [5,7,8]
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