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Aging is the principal risk factor for cardiovascular disease (CVD), the leading cause of death worldwide. The yearly death toll from CVD is 17.7 million people, representing 31% of all deaths (www.who.int/ cardiovascular_diseases). Most clinical manifestations of CVD (e.g. myocardial infarction and stroke) derive from atherosclerosis, which is characterized by thickening of the arterial wall and luminal narrowing due to atherosclerotic plaque accumulation. Accelerated atherosclerosis is a key feature of Hutchinson-Gilford progeria syndrome (HGPS), an ultrarare genetic disorder caused by a de novo heterozygous point mutation (c.1824C>T; p.G608G) in the LMNA gene, resulting in the expression of a toxic form of lamin A called progerin [1]. Affected children prematurely manifest features of aging, such as skin abnormalities, alopecia, lipodystrophy, joint stiffness, and reduced bone density. Although most HGPS patients lack classical cardiovascular risk factors, they typically die from atherosclerosis complications at an average age of 14.6 years. Thus, HGPS gives us an exceptional opportunity to study CVD independently of classical risk factors such as elevated low-density cholesterol and tobacco smoking [2]. To facilitate research into HGPS, several mouse models have been developed that resemble many features of the human disease [2]. However, none of the available models develops atherosclerosis, the death-causing symptom of this devastating disease. To bridge this gap, we generated an atherosclerosis-prone HGPS-like mouse model [3] by crossing progeroid Lmna knock-in mice [4] with atherosclerotic Apoe knockout mice. Similar to HGPS patients, progeroid Apoe Lmna mice have a severe premature aging phenotype with impaired postnatal growth and a shortened lifespan (median survival 4.5 months, compared with 29.4 months for control mice). Importantly, ApoeLmna mice have a higher atherosclerosis burden than control Apoe mice with a wildtype Lmna gene, despite having similar serum cholesterols levels. ApoeLmna mice also develop other vascular pathologies previously detected in postmortem specimens from HGPS patients [5], including vascular smooth muscle cell (VSMC) loss in the media and adventitial thickening. We also found lipid deposits in the medial aorta of these mice, a phenomenon not described before. All these vascular Editorial

Accelerated atherosclerosis in HGPS