Research ArticleProgeria

Disrupting the LINC complex in smooth muscle cells reduces aortic disease in a mouse model of Hutchinson-Gilford progeria syndrome

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Science Translational Medicine  26 Sep 2018:
Vol. 10, Issue 460, eaat7163
DOI: 10.1126/scitranslmed.aat7163

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Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare disorder of accelerated aging caused by mutations in lamin, exhibit vascular complications. Kim et al. investigated the mechanism responsible for vascular smooth muscle cell death and aortic disease using HGPS mice. They found that smooth muscle cells expressing progerin (truncated form of lamin produced by mutations in lamin) became apoptotic under stretch. HGPS mice exhibited greater disease burden in the inner curvature of the aorta and at vascular branch regions. Disrupting the transmission of force between the cytoskeleton and nucleus abrogated apoptosis in progerin-expressing smooth muscle cells. These results highlight the role of shear stress in contributing to vascular disease in HGPS.

Abstract

Hutchinson-Gilford progeria syndrome is a disorder of premature aging in children caused by de novo mutations in LMNA that lead to the synthesis of an internally truncated form of prelamin A (commonly called progerin). The production of progerin causes multiple disease phenotypes, including an unusual vascular phenotype characterized by the loss of smooth muscle cells in the arterial media and fibrosis of the adventitia. We show that progerin expression, combined with mechanical stress, promotes smooth muscle cell death. Disrupting the linker of the nucleoskeleton and cytoskeleton (LINC) complex in smooth muscle cells ameliorates the toxic effects of progerin on smooth muscle cells and limits the accompanying adventitial fibrosis.

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