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

• DOI: 10.1073/pnas.2400752121
• Publication Date: 2024-04-22T19:06:28Z
• Authors: Ignacio Benedicto; Rosa M. Carmona; Ana Barettino; Carla Espinós-Est...; Pilar Gonzalo; Rosa M. Nevado; Miguel de la Fuen...; María J. Andrés-M...; Cristina González...; Loïc Rolas; Beatriz Dorado; Sussan Nourshargh; Magda R. Hamczyk; Vicente Andrés
• Keywords: Male; Hutchinson–Gilford progeria syndrome; Endothelial cells; Myocytes, Smooth Muscle; Endothelial Cells; Mice, Transgenic; Biological Sciences; Atherosclerosis; Lamin Type A; Muscle, Smooth, Vascular; Mice; Disease Models, Animal; Progeria; Vascular smooth muscle cells; Animals; Humans; Proprotein Convertase 9

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 HGPSrev-Cdh5-CreERT2 and HGPSrev-SM22α-Cre mice with progerin suppression in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), respectively. HGPSrev-Cdh5-CreERT2 mice were undistinguishable from HGPSrev mice with ubiquitous progerin expression, in contrast with the ameliorated progeroid phenotype of HGPSrev-SM22α-Cre mice. To study atherosclerosis, we generated atheroprone mouse models by overexpressing a PCSK9 gain-of-function mutant. While HGPSrev-Cdh5-CreERT2 and HGPSrev mice developed a similar level of excessive atherosclerosis, plaque development in HGPSrev-SM22α-Cre 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.