Journal
EMBO MOLECULAR MEDICINE
Volume 11, Issue 4, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201809736
Keywords
aging; endoplasmic reticulum stress; progeria; unfolded protein response; vascular smooth muscle cell
Categories
Funding
- Spanish Instituto de Salud Carlos III [RD12/0042/0028, AC17/00067, AC16/00091]
- Ministerio de Ciencia, Innovacion y Universidades (MCIU) [SAF2016-79490-R]
- Fondo Europeo de Desarrollo Regional (FEDER, Una manera de hacer Europa)
- Progeria Research Foundation [2014-52]
- Fundacio Marato TV3 [122/C/2015]
- MCIU
- Pro CNIC Foundation
- Severo Ochoa Center of Excellence [SEV-2015-0505]
- Ministerio de Economia y Competitividad (MINECO/FEDER)
- European Research Council
- Progeria Research Foundation
- Obra Social Cajastur
- Intramural Research Program of the National Institutes of Health, National Cancer Institute
- Center for Cancer Research
- MCIU [JCI-2011-09663, SAF-2014-60699-JIN, FJCI-2017-33299, BES-2011-043938]
- Ministerio de Educacion, Cultura y Deporte (FPU) [FPU16/05027]
- Principado de Asturias
- MINECO
- FEDER
- Erwin Schroedinger Fellowship from the Austrian Science Fund [J3849-B28]
- NATIONAL CANCER INSTITUTE [ZIABC010309] Funding Source: NIH RePORTER
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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.
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