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oai:repisalud.isciii.es:20.500.12105/75102024-09-27T08:22:13Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Hamczyk, Magda R. author Villa-Bellosta, Ricardo author Quesada, Víctor author Gonzalo, Pilar author Vidak, Sandra author Nevado, Rosa M author Andres-Manzano, Maria J. author Misteli, Tom author López-Otín, Carlos author Andres, Vicente author 2019-04 Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant lamin A variant. HGPS patients display accelerated aging and die prematurely, typically from atherosclerosis complications. Recently, we demonstrated that progerin-driven vascular smooth muscle cell (VSMC) loss accelerates atherosclerosis leading to premature death in apolipoprotein E-deficient mice. However, the molecular mechanism underlying this process remains unknown. Using a transcriptomic approach, we identify here endoplasmic reticulum stress (ER) and the unfolded protein responses as drivers of VSMC death in two mouse models of HGPS exhibiting ubiquitous and VSMC-specific progerin expression. This stress pathway was also activated in HGPS patient-derived cells. Targeting ER stress response with a chemical chaperone delayed medial VSMC loss and inhibited atherosclerosis in both progeria models, and extended lifespan in the VSMC-specific model. Our results identify a mechanism underlying cardiovascular disease in HGPS that could be targeted in patients. Moreover, these findings may help to understand other vascular diseases associated with VSMC death, and provide insight into aging-dependent vascular damage related to accumulation of unprocessed toxic forms of lamin A. EMBO Mol Med. 2019; 11(4):e9736 10.15252/emmm.201809736 1757-4684 1757-4676 EMBO molecular medicine 30862662 http://hdl.handle.net/20.500.12105/7510 Aging Endoplasmic reticulum stress Progeria Unfolded protein response Vascular smooth muscle cell Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells