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 February 1, 2019; First published November 13, 2018
Citation Information: J Clin Invest. 2019;129(2):531-545. https://doi.org/10.1172/JCI121297.
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Categories: Research Article Aging Cell biology

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 8

Working model.

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Working model. Progerin accumulation at the nuclear lamina leads to pert...
Progerin accumulation at the nuclear lamina leads to perturbations in F-actin level and actin organization and defects in components involved in nucleocytoskeletal coupling (SUN1/2 and emerin). The defective rigid nucleocytoskeletal links show impaired mechanoresponse and cause MRTFA accumulation at the nuclear periphery. MRTFA or associated complexes exert presumably a positive feedback loop on Actb expression (looped arrow). These changes set off the profibrotic signaling cascade (indicated by pale orange color of the nucleus), such as downregulation of eNOS and reduced secretion of NO. Absence of endothelium-derived atheroprotective NO and presumably other unidentified factors leads to increased collagen production in other cell types as shown for fibroblasts through a switch to myofibroblasts, leading to collagen deposition and cardiac fibrosis.