Exacerbated atherosclerosis in progeria is prevented by progerin elimination in vascular smooth muscle cells but not endothelial cells.

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease caused by the expression of progerin, a mutant protein that accelerates aging and precipitates death. Given that atherosclerosis complications are the main cause of death in progeria, here, we investigated whether progerin-induced atherosclerosis is prevented in <i>HGPSrev-Cdh5-CreERT2</i> and <i>HGPSrev-SM22α-Cre</i> mice with progerin suppression in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), respectively. <i>HGPSrev-Cdh5-CreERT2</i> mice were undistinguishable from <i>HGPSrev</i> mice with ubiquitous progerin expression, in contrast with the ameliorated progeroid phenotype of <i>HGPSrev-SM22α-Cre</i> mice. To study atherosclerosis, we generated atheroprone mouse models by overexpressing a PCSK9 gain-of-function mutant. While <i>HGPSrev-Cdh5-CreERT2</i> and <i>HGPSrev</i> mice developed a similar level of excessive atherosclerosis, plaque development in <i>HGPSrev-SM22α-Cre</i> mice was reduced to wild-type levels. Our studies demonstrate that progerin suppression in VSMCs, but not in ECs, prevents exacerbated atherosclerosis in progeroid mice.