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Data from: Paradoxical aortic stiffening and subsequent cardiac dysfunction in Hutchinson–Gilford progeria syndrome

Citation

Murtada, Sae-Il et al. (2020), Data from: Paradoxical aortic stiffening and subsequent cardiac dysfunction in Hutchinson–Gilford progeria syndrome, Dryad, Dataset, https://doi.org/10.5061/dryad.mcvdncjw9

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is an ultra-rare disorder with devastating sequelae resulting in early death, presently thought to stem primarily from cardiovascular events. We analyse novel longitudinal cardiovascular data from a mouse model of HGPS (LmnaG609G/G609G) using allometric scaling, biomechanical phenotyping, and advanced computational modelling and show that late-stage diastolic dysfunction, with preserved systolic function, emerges with an increase in the pulse wave velocity and an associated loss of aortic function, independent of sex. Specifically, there is a dramatic late-stage loss of smooth muscle function and cells and an excessive accumulation of proteoglycans along the aorta, which result in a loss of biomechanical function (contractility and elastic energy storage) and a marked structural stiffening despite a distinctly low intrinsic material stiffness that is consistent with the lack of functional lamin A. Importantly, the vascular function appears to arise normally from the low-stress environment of development, only to succumb progressively to pressure-related effects of the lamin A mutation and become extreme in the peri-morbid period. Because the dramatic life-threatening aortic phenotype manifests during the last third of life there may be a therapeutic window in maturity that could alleviate concerns with therapies administered during early periods of arterial development.

Funding

National Institute on Aging, Award: R01 AG047632

National Heart, Lung, and Blood Institute, Award: P01 HL134605,R01 HL105297

National Institute of Environmental Health Sciences, Award: R33 ES025636