![The development of exacerbated atherosclerosis in the aorta of progeroid mice (top image) is prevented by removing progerin in vascular smooth muscle cells (bottom image). The development of exacerbated atherosclerosis in the aorta of progeroid mice (top image) is prevented by removing progerin in vascular smooth muscle cells (bottom image).](/sites/default/files/2024-04/imagen_web_2.jpg)
A study published in the journal The Proceedings of the National Academy of Sciences (PNAS), with the participation of Dr. Ignacio Benedicto, who recently joined the Margarita Salas Center for Biological Research (CSIC), demonstrates that the elimination of progerin in vascular smooth muscle cells, but not in endothelial cells, prevents atherosclerosis associated with Hutchinson-Gilford progeria syndrome (HGPS). The study was carried out with the group of Dr. Vicente Andrés, from the National Center for Cardiovascular Research (CNIC) and in collaboration with the University of Oviedo and Queen Mary University of London.
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease that affects 1 in 20 million people - estimated to affect fewer than 400 children worldwide - and is characterized by accelerated aging, severe atherosclerosis, and premature death at an average age of approximately 15 years. Although HGPS patients do not usually have the typical cardiovascular risk factors (hypercholesterolemia, obesity, smoking, etc.), their main cause of death is complications of atherosclerosis, such as myocardial infarction, stroke, or heart failure. Since there is currently no cure for progeria, it is urgent to develop new therapies that prevent atherosclerosis and other vascular alterations associated with the disease to increase the life expectancy of patients.
The genetic cause of HGPS is a mutation in the LMNA gene that causes the expression of progerin, a mutant version of the nuclear protein lamin A that induces numerous harmful effects at the cellular and organismal levels.
Recent studies in animal models of this syndrome have shown that it is possible to correct this mutation by gene editing and that the subsequent elimination of progerin and recovery of lamin A expression improves the characteristic alterations of HGPS and prolongs life expectancy.
To optimize gene therapy for the potential treatment of progeria patients, it is important to identify the cell types in which progerin deletion produces the most benefit.
To address this question, the laboratory of Dr. Vicente Andrés, from the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and CIBER de Enfermedades Cardiovasculares (CIBERCV), had previously generated the HGPSrev mouse. The results of this study were published in the journal Circulation and pointed to vascular smooth muscle cells as a possible therapeutic target to combat premature atherosclerosis in progeria.
"This model of progeria expresses progerin and lamina A deficiency in the whole organism, and allows the elimination of progerin and the restoration of lamina A in specific cell types and at different stages of the disease," explains Dr. Andrés.
In this work, HGPSrev mice are used to study whether HGPS-associated atherosclerosis can be prevented by progerin deletion and lamin A restoration in endothelial cells or vascular smooth muscle cells, "two cell types of the arterial wall that play a key role in the development of conventional atherosclerosis," explains Dr. Benedicto.
The researchers found that deletion of progerin in endothelial cells did not provide any benefit. Atherosclerosis, arterial fibrosis, vascular inflammation, weight loss, and premature death were observed in these mice in a manner identical to mice with whole-body progerin expression. In contrast, those HGPSrev mice that had progerin deleted in vascular smooth muscle cells showed a level of atherosclerosis identical to that developed by control mice without progerin expression and also had no excess arterial fibrosis and vascular inflammation.
"These results suggest that correction of the HGPS-causing mutation in vascular smooth muscle cells may be sufficient to produce a significant therapeutic benefit," Dr. Benedicto stresses. "Such a strategy would likely require lower doses of gene-editing reagents than those needed for whole-organism progerin deletion, which could increase the possibility of developing more effective and safer future clinical applications," concludes Dr. Andres, “further research is needed to advance our understanding of the mechanisms by which progerin accelerates aging and to develop new therapies and, eventually, a cure for this disease."
Reference: Exacerbated atherosclerosis in progeria is prevented by progerin elimination in vascular smooth muscle cells but not endothelial cells. Ignacio Benedicto, Rosa M. Carmona, Ana Barettino, …, Vicente Andrés (2024) PNAS 121 (18) e2400752121. https://doi.org/10.1073/pnas.2400752121
More information:
CNIC Press Release: link.