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Endothelial Dysfunction and the Pathobiology of Accelerated Atherosclerosis in Hutchinson‐Gilford Progeria Syndrome
Author(s) -
Yap Belinda,
GarciaCardena Guillermo,
Gimbrone Michael A.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.471.11
Subject(s) - progeria , endothelial dysfunction , proinflammatory cytokine , endothelial activation , biology , premature aging , pdgfb , downregulation and upregulation , microbiology and biotechnology , cancer research , endothelium , endocrinology , immunology , inflammation , genetics , growth factor , gene , platelet derived growth factor receptor , receptor
A prominent feature of Hutchinson‐Gilford Progeria Syndrome (HGPS) is premature, severe atherosclerosis, resulting in fatal heart attacks and strokes. Given the critical role of endothelial dysfunction in atherogenesis, we explored the effects of progerin (the mutant gene product in HGPS) on endothelial pathobiology, utilizing a model system in which cultured human endothelial cells (EC) express progerin via adenoviral infection. Progerin accumulation in EC results in a strikingly abnormal nuclear morphology, observed as aggregation of progerin and other nuclear proteins. Accumulation of progerin also induces a proinflammatory/atherogenic program of EC activation characterized by 1) sustained expression of leukocyte adhesion molecules (VCAM‐1, E‐selectin) and proinflammatory cytokines (IL‐8, MCP‐1); 2) expression of prothrombotic genes (PAI‐1); 3) decreased expression of eNOS; and 4) downregulation of KLF2, a transcription factor critical to endothelial homeostasis. Further, conditioned medium from progerin‐expressing EC induces dysfunction when transferred onto control EC. Thus, progerin accumulation in EC appears to induce a state of chronic dysfunction, via autocrine/paracrine pathways, potentially contributing to the premature and accelerated atherosclerosis of HGPS.