Vascular Smooth Muscle–Specific Progerin Expression Accelerates Atherosclerosis and Death in a Mouse Model of Hutchinson-Gilford Progeria Syndrome

Abstract

Supplemental Digital Content is available in the text.

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

“…However, TUDCA did not prolong lifespan in Apoe −/− Lmna G609G/G609G mice with ubiquitous progerin expression. This is in accordance with previous observations that, unlike HGPS patients, these mutant mice apparently die from atherosclerosis‐independent causes, possibly arrhythmias, starvation, and cachexia (Hamczyk et al , ; Kreienkamp et al , ). In contrast to Apoe −/− Lmna G609G/G609G mice, Apoe −/− Lmna LCS/LCS SM22αCre mice most likely die from atherosclerosis‐related causes (Hamczyk et al , ).…”

“…TUDCA treatment alleviated aortic VSMC loss (Fig A and B), adventitial thickening (Fig C and D), and inhibited atherosclerosis (Fig E and F) in both Apoe −/− Lmna G609G/G609G and Apoe −/− Lmna LCS/LCS SM22αCre mice. Atheromas of TUDCA‐treated progeroid animals showed reduced necrotic core size and increased VSMC content (), indicating an amelioration of the vulnerable plaque phenotype reported previously in these mice (Hamczyk et al , ). We next assessed the effect of a sustained TUDCA treatment on survival in normal chow‐fed progeroid mice.…”

“…However, only a few studies have investigated the molecular alterations caused by progerin accumulation in VSMCs (Zhang et al , , ; Villa‐Bellosta et al , ; Hamczyk et al , ), and none analyzed it in the context of atherosclerosis, the main death‐causing symptom of HGPS, due to lack of adequate animal models. Recently, we have generated an HGPS‐like mouse model of ubiquitous progerin expression that reproduces the main features of human HGPS, including VSMC loss in the aortic media, adventitial thickening, accelerated atherosclerosis, and shortened lifespan (Hamczyk et al , ). Moreover, we have shown that limiting progerin expression to VSMCs is sufficient to cause the loss of these cells in the aorta and accelerate atherosclerosis and death, demonstrating a key role of VSMCs in the pathogenesis of HGPS (Hamczyk et al , ).…”

Endoplasmic reticulum stress at the crossroads of progeria and atherosclerosis

“…Considering the role that macrophages have in atherosclerosis, it is surprising that mice with macrophage‐restricted progerin expression did not present with an HGPS phenotype (Hamczyk et al , ). Zhou et al () have shown activation of ER stress/UPR‐related pathways in macrophages recruited to the vascular lesions in ApoE −/− mice, but UPR was mainly triggered by lipid accumulation, at least at later stages.…”

“…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.…”