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

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.

Endoplasmic reticulum stress at the crossroads of progeria and atherosclerosis

“…Alterations of the ER are known to play an important role in macrophages, key immune effectors in vascular lesions; however, this pathway has never been associated before with progerin‐mediated responses in isolated VSMCs. In their study, Hamczyk et al () show that upstream regulators of UPR pathways are activated in progerin‐expressing VSMCs. Indeed, they found activation of genes downstream of the main UPR sensors IRE1 and PERK; cell death was the consequence, leading to the VSMC loss observed in the progeric mice.…”

“…Interestingly, in a very early phase, UPR activation in macrophages appears to be independent of lipid accumulation, suggesting involvement of other pathophysiological factors, such as inflammatory cells or signals from ECs (Zhou et al , ). The study by Hamczyk et al () demonstrates that the activation of this pathway may occur through a cell‐autonomous mechanism in progerin‐expressing VSMCs, without intervention of paracrine factors or activation of the immune system, and that this probably takes place secondarily together with activation of the cell death program. Both progerin accumulation and ER stress are associated with inflammation, two processes strictly dependent upon each other.…”

“…Progeric cells and HGPS mouse models have elevated NF‐kB activation and increased levels of inflammatory markers and cytokines, findings that support a link between the nuclear lamina and inflammation, and thus indicative of a central role of inflammation in accelerated aging (Osorio et al , ). However, although the activation of an adaptive inflammatory response is likely to occur also in progerin‐expressing VSMCs, data from RNA sequencing shown by Hamczyk et al () identify the ER stress response and the UPR as the two most prominent pathways in HGPS‐related atherosclerosis.…”

“…Finally, the authors demonstrate that alleviation of ER stress is sufficient to reduce VSMC loss in the aorta: Indeed, administration of the chemical chaperon tauroursodeoxycholic acid (TUDCA) inhibited pro‐apoptotic gene expression, blunted atherosclerosis progression, and prolonged the lifespan of mice with VSMC‐selective progerin expression (Hamczyk et al , ), which most likely die from atherosclerosis‐related causes (Hamczyk et al , ). This is a particularly important finding since it confirms the therapeutic value of intervening at the two pathways in VSMCs.…”

“…Atherosclerosis is one of the most severe and clinically relevant features of HGPS , manifesting in the absence of classical risk factors, such as increased low‐density lipoprotein and C‐reactive protein (Gordon et al , ). In this issue, Hamczyk et al () describe a mechanism for HGPS ‐related atherosclerosis.…”