Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells.

Magda R Hamczyk,Víctor Quesada,Tom Misteli,Sandra Vidak,María J Andrés‐Manzano,Pilar Gonzalo,Ricardo Villa‐Bellosta,Vicente Andrés,Carlos López‐Otín,Rosa M Nevado

doi:10.15252/emmm.201809736

Abstract

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.

Highlights

Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant lamin A variant
Given the importance of vascular smooth muscle cell (VSMC) in progerin-driven cardiovascular disease (Stehbens et al, 2001; Olive et al, 2010; Hamczyk et al, 2018b), we sought to identify mechanisms underlying VSMC death and enhanced atherosclerosis in HGPS, which seem to be independent of elevated cholesterol levels in the blood (Gordon et al, 2005; Hamczyk et al, 2018b)
Our RNA sequencing (RNAseq) analysis of pre-disease aortic medial cells from the ubiquitous and VSMC-specific progeria models identified for the first time the endoplasmic reticulum stress (ER) stress response and the related unfolded protein response (UPR) as potential driver mechanisms of VSMC death and the subsequent atherosclerosis in progeria

Summary

Introduction

Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant lamin A variant. 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 activated in HGPS patient-derived cells. Our results identify a mechanism underlying cardiovascular disease in HGPS that could be targeted in patients. 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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