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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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Research Article Aging Cell biology Article has an altmetric score of 34

Endothelial progerin expression causes cardiovascular pathology through an impaired mechanoresponse

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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 1

Characterization of Prog-Tg mice.

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Characterization of Prog-Tg mice.
(A) Immunoblots of indicated lysates u...
(A) Immunoblots of indicated lysates using anti–human lamin A/C (detecting transgenes, upper panel), anti–lamin A/C (recognizing human and mouse lamin A/C, lower panel), and anti-tubulin and anti–VE-cadherin as loading controls. Numbers show ratio of total lamin A levels in transgenic over Wt animals. Endothelial cells (ECs) from Wt (Wt-EC), Prog-Tg (Prog-Tg-EC) and LA-Tg (LA-Tg-EC) animals; EC-depleted cell mixture from Prog-Tg animals (Prog-Tg-non-EC); and HGPS patient fibroblasts (HGPS) were analyzed. (B) Histogram of mean progerin fluorescence intensities in immunofluorescence images of Prog-Tg ECs (see Figure 5C) (n = 5 Prog-Tg mice, 462 cells in total). (C and D) Immunofluorescence images of coronary artery (C) and cardiac tissue (D) from Prog-Tg animals stained with antibodies against progerin, VE-cadherin (note green autofluorescence of elastic lamina), and PECAM1, and Hoechst (representative of n = 3 Prog-Tg animals). Progerin expression is confined to the intimal layer (C, arrowheads) and PECAM1-positive cardiac microvasculature (D, arrowheads). Dashed lines, cardiomyocyte boundaries; arrows, intima (C) and progerin-negative cardiomyocytes (D). Scale bars: 10 μm. (E) Body weight over time for male and female Prog-Tg and LA-Tg versus Wt littermates. Two-way repeated-measures ANOVA revealed a significant impact for the Prog-Tg genotype (females F = 72.6, P < 0.001, males F = 65.3, P < 0.001, n = 6 littermate pairs), but not for the LA-Tg genotype (females F = 0.517, P = 0.493; males F = 0.221, P = 0.651, n = 5 littermate pairs). Comparison of Prog-Tg versus Wt revealed at least P < 0.01 (Holm-Sidak method) for females and males at more than 5 and 8 weeks, respectively. (F) Kaplan-Meier survival plot showing significantly reduced life span of Prog-Tg mice (n = 12) versus Wt littermate controls (n = 20) and LA-Tg mice (n = 8). P < 0.0001, log-rank (Mantel-Cox) test; pairwise comparison with Bonferroni’s correction of threshold showed significant difference in survival of Prog-Tg compared with control, Prog-Tg with LA-Tg, but not LA-Tg with control mice. Data presented as mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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