Progerin Expression Induces Inflammation, Oxidative Stress and Senescence in Human Coronary Endothelial Cells

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a rare premature aging disorder notably characterized by precocious and deadly atherosclerosis. Almost 90% of HGPS patients carry a LMNA p.G608G splice variant that leads to the expression of a permanently farnesylated abnormal form of prelamin-A, referred to as progerin. Endothelial dysfunction is a key determinant of atherosclerosis, notably during aging. Previous studies have shown that progerin accumulates in HGPS patients’ endothelial cells but also during vascular physiological aging. However, whether progerin expression in human endothelial cells can recapitulate features of endothelial dysfunction is currently unknown. Herein, we evaluated the direct impact of exogenously expressed progerin and wild-type lamin-A on human endothelial cell function and senescence. Our data demonstrate that progerin, but not wild-type lamin-A, overexpression induces endothelial cell dysfunction, characterized by increased inflammation and oxidative stress together with persistent DNA damage, increased cell cycle arrest protein expression and cellular senescence. Inhibition of progerin prenylation using a pravastatin–zoledronate combination partly prevents these defects. Our data suggest a direct proatherogenic role of progerin in human endothelial cells, which could contribute to HGPS-associated early atherosclerosis and also potentially be involved in physiological endothelial aging participating to age-related cardiometabolic diseases.

Interleukin‐6 neutralization ameliorates symptoms in prematurely aged mice

“…Consistent with previous studies (Bidault et al, 2020;Liu et al, 2019), we observed that IL6 secretion is increased in HGPS fibroblasts carrying the classical G608G LMNA mutation and also in fibroblasts from Mandibuloacral Dysplasia, another LMNAlinked progeroid syndrome (Cenni et al, 2018;Filesi et al, 2005) ( Figure 1a and Figure S1a). Further, the LMNA delta 50 mutation causing progerin expression, when transiently expressed in human HEK293 cells, induced hypersecretion of IL6 ( Figure 1b).…”

“…The moderate increase in life span obtained by tocilizumab administration suggests that pathogenetic pathways specifically relevant to animal survival were not rescued. For instance, despite amelioration of adipose tissue turnover and attenuation of IL6 signaling, metabolic effects related to dysregulation of other cytokines (Bidault et al, 2020; Griveau et al, 2020; Liu et al, 2019) might suddenly establish a fatal condition. Optimization of tocilizumab dosage and combination with drugs or molecular approaches already explored for HGPS treatment may pave the way to effective therapeutic strategies (Cenni et al, 2020; Liu et al, 2019).…”

“…Cell intrinsic and cell-independent mechanisms play a synergistic role in HGPS pathogenesis (Bidault et al, 2020;Del Campo et al, 2019;Cenni et al, 2020;Kreienkamp et al, 2016Kreienkamp et al, , 2018Kreienkamp et al, , 2019Kreienkamp & Gonzalo, 2020;Osmanagic-Myers et al, 2019). Thus, an efficient therapeutic strategy needs to counteract both mechanism types.…”

Coronary Endothelium No‐Reflow Injury Is Associated with ROS‐Modified Mitochondrial Fission through the JNK‐Drp1 Signaling Pathway

“…In the present study, we found that ROS are induced by H/R injury in CECs and correlate with the survival of CECs by mediating mitochondrial bioenergetics. Similarly, it was previously reported that ischemia/reperfusion-mediated senescence and vascular dysfunction of endothelial cells were attenuated by oxidants [61]. Endothelial cell necroptosis is also induced by ROS-mediated opening of the mitochondrial permeability transition pore (mPTP) [62].…”

NLRP3 inflammasome inhibition rescues Hutchinson-Gilford Progeria cellular phenotype and extend longevity of an animal model

“…In this context, cardiovascular diseases have been shown accelerated in HGPS patients and progerin, the abnormal form of prelamin-A, has also been shown to induces atherosclerosis and cardiac electrophysiological alterations (14). Furthermore, exogenously expressed progerin was showed increases inflammation (15). On the other hand, the AIM2 inflammasome has been shown to be activated after pharmacological alterations of the nuclear envelope integrity compatible with laminopathies (16).…”