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J Clin Invest. 2019 Feb 1;129(2):531-545. doi: 10.1172/JCI121297. Epub 2018 Dec 18.

Endothelial progerin expression causes cardiovascular pathology through an impaired mechanoresponse.

Author information

1
Max F. Perutz Laboratories (MFPL), Department of Medical Biochemistry, Medical University of Vienna and University of Vienna, Vienna Biocenter (VBC), Vienna, Austria.
2
Department of Biotechnology, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria.
3
Ludwig Boltzmann Cluster for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, Vienna, Austria.
4
Department of Biosciences and Nutrition, Karolinska Institutet, NEO, Huddinge, Sweden.

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.

KEYWORDS:

Aging; Cell Biology; Fibrosis; Mouse models; endothelial cells

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