Endothelial progerin expression causes cardiovascular pathology through an impaired mechanoresponse
Selma Osmanagic-Myers, … , Maria Eriksson, Roland Foisner
Selma Osmanagic-Myers, … , Maria Eriksson, Roland Foisner
Published November 13, 2018
Citation Information: J Clin Invest. 2019;129(2):531-545. https://doi.org/10.1172/JCI121297.
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Endothelial progerin expression causes cardiovascular pathology through an impaired mechanoresponse

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder characterized by accelerated cardiovascular disease with extensive fibrosis. It is caused by a mutation in LMNA leading to expression of truncated prelamin A (progerin) in the nucleus. To investigate the contribution of the endothelium to cardiovascular HGPS pathology, we generated an endothelium-specific HGPS mouse model with selective endothelial progerin expression. Transgenic mice develop interstitial myocardial and perivascular fibrosis and left ventricular hypertrophy associated with diastolic dysfunction and premature death. Endothelial cells show impaired shear stress response and reduced levels of endothelial nitric oxide synthase (eNOS) and NO. On the molecular level, progerin impairs nucleocytoskeletal coupling in endothelial cells through changes in mechanoresponsive components at the nuclear envelope, increased F-actin/G-actin ratios, and deregulation of mechanoresponsive myocardin-related transcription factor-A (MRTFA). MRTFA binds to the Nos3 promoter and reduces eNOS expression, thereby mediating a profibrotic paracrine response in fibroblasts. MRTFA inhibition rescues eNOS levels and ameliorates the profibrotic effect of endothelial cells in vitro. Although this murine model lacks the key anatomical feature of vascular smooth muscle cell loss seen in HGPS patients, our data show that progerin-induced impairment of mechanosignaling in endothelial cells contributes to excessive fibrosis and cardiovascular disease in HGPS patients.

Authors

Selma Osmanagic-Myers, Attila Kiss, Christina Manakanatas, Ouafa Hamza, Franziska Sedlmayer, Petra L. Szabo, Irmgard Fischer, Petra Fichtinger, Bruno K. Podesser, Maria Eriksson, Roland Foisner

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Figure 6

Defective nucleocytoskeletal connections in Prog-Tg cells.

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Defective nucleocytoskeletal connections in Prog-Tg cells. (A) ECs from ...
(A) ECs from Wt and Prog-Tg mice were immunostained with progerin and SUN1 antibodies and DNA dye (DAPI). Arrowheads, cells with high progerin levels show stronger SUN1 staining (images are representative of n = 3 independent experiments). Scale bar: 10 μm. Box plots show the distribution of SUN1 mean fluorescence intensities in Prog-Tg versus Wt ECs (n = 100 cells per genotype). Data presented as median (middle line) with boxes encompassing 25th to 75th percentile, and whiskers, minimum to maximum values. *P < 0.05 by Mann-Whitney U test. Lower panel, mean progerin fluorescence intensities plotted over mean SUN1 fluorescence intensities in Prog-Tg cells. Arbitrary units (AU) of fluorescence, n = 101 cells. (B) Quantitative immunoblot analysis of Wt and Prog-Tg endothelial cell lysates (n = 6 for Wt and n = 3 for Prog-Tg independent experiments). **P < 0.01. (C) Projections of confocal Z stacks of Wt and Prog-Tg ECs stained for emerin. Scale bar: 10 μm. Right panel, immunoblot for emerin and tubulin (loading control, images representative of n = 3 independent experiments). (D) Wt and Prog-Tg ECs processed for immunofluorescence microscopy using Atto 488–labeled phalloidin and Texas Red–labeled DNase I, quantitatively evaluated to obtain the F-actin/G-actin ratio (n = 4 independent experiments). Arrow, actin “knots” in Prog-Tg cells. Scale bar: 10 μm. Lower right, expression levels of actin (Actb) in heart tissue (age ~24 weeks, n = 5 littermate pairs) and ECs (n = 4 independent experiments) from Prog-Tg and Wt littermates. Values were normalized to Hprt. *P < 0.05, **P < 0.01 by paired (littermate tissue) and unpaired (cells) Student’s t test (B and D). Data presented as mean ± SEM.