Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Progerin Expression Induces Inflammation, Oxidative Stress and Senescence in Human Coronary Endothelial Cells. 3240 87

The main actors of this review are Hutchinson-Gilford progeria syndrome (HGPS) and atherosclerosis. HGPS is a very rare disease with no definitively approved specific drugs. Atherosclerosis is a very common disease with a more consolidated treatment strategy. Nevertheless, common mechanisms are shared by both these diseases, particularly related to inflammation, oxidative and endoplasmic reticulum (ER) stress. Pathways regulated by Nuclear factor E2 related factor (Nrf2), Nuclear factor kappa B (NF-kB) and related to the Unfolded Protein Response (UPR) and ER stress are receiving increasing attention. In HGPS "not omnia" happen(s) "cum tempore", that means that HGPS patients have atherosclerotic complications before their time. The third actor is clonal hematopoiesis: it constitutes a link between ageing and atherosclerosis. This review aims to analyse the current knowledge of atherosclerosis and clonal hematopoiesis in order to suggest therapeutic strategies to correct the timing of the atherosclerosis progression in HGPS. The goal for HGPS is a shift from "not omnia cum tempore" to "omnia cum tempore" in terms of significant lifespan extension by postponing atherosclerosis-related complications.
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PMID:Progeria, atherosclerosis and clonal hematopoiesis: links and future perspectives. 3300 46

Hutchinson-Gilford progeria syndrome (HGPS) is among the most devastating of the laminopathies, rare genetic diseases caused by mutations in genes encoding nuclear lamina proteins. HGPS patients age prematurely and die in adolescence, typically of atherosclerosis-associated complications. The mechanisms of HGPS-related atherosclerosis are not fully understood due to the scarcity of patient-derived samples and the availability of only one atheroprone mouse model of the disease. Here, we generated a new atherosusceptible model of HGPS by crossing progeroid LmnaG609G/G609G mice, which carry a disease-causing mutation in the Lmna gene, with Ldlr-/- mice, a commonly used preclinical atherosclerosis model. Ldlr-/-LmnaG609G/G609G mice aged prematurely and had reduced body weight and survival. Compared with control mice, Ldlr-/-LmnaG609G/G609G mouse aortas showed a higher atherosclerosis burden and structural abnormalities typical of HGPS patients, including vascular smooth muscle cell depletion in the media, adventitial thickening, and elastin structure alterations. Atheromas of Ldlr-/-LmnaG609G/G609G mice had features of unstable plaques, including the presence of erythrocytes and iron deposits and reduced smooth muscle cell and collagen content. Ldlr-/-LmnaG609G/G609G mice faithfully recapitulate vascular features found in patients and thus provide a new tool for studying the mechanisms of HGPS-related atherosclerosis and for testing therapies.
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PMID:Premature Vascular Aging with Features of Plaque Vulnerability in an Atheroprone Mouse Model of Hutchinson-Gilford Progeria Syndrome with Ldlr Deficiency. 3304 78


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