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.