Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase.

Ryan Von Kleeck,Emilia Roberts,Richard K Assoian,Elizabeth A Hawthorne,Paola Castagnino,Kyle Bruun,Tina Xu,John W Tobias,Sonja A Brankovic

doi:10.26508/lsa.202000997

Ryan Von Kleeck, Emilia Roberts + Show 7 more

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https://doi.org/10.26508/lsa.202000997

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Abstract

Arterial stiffening and cardiac dysfunction are hallmarks of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LaminAG609G mouse model of HGPS recapitulates the premature arterial stiffening and early diastolic dysfunction seen in human HGPS. Lysyl oxidase (LOX) is up-regulated in the arteries of these mice, and treatment with the LOX inhibitor, β-aminopropionitrile, improves arterial mechanics and cardiac function. Genome-wide and mechanistic analysis revealed reduced expression of the LOX-regulator, miR-145, in HGPS arteries, and forced expression of miR-145 restores normal LOX gene expression in HGPS smooth muscle cells. LOX abundance is also increased in the carotid arteries of aged wild-type mice, but its spatial expression differs from HGPS and its up-regulation is independent of changes in miR-145 abundance. Our results show that miR-145 is selectively misregulated in HGPS and that the consequent up-regulation of LOX is causal for premature arterial stiffening and cardiac dysfunction.

Highlights

Hutchinson–Gilford Progeria Syndrome (HGPS) is a rare genetic disease of premature aging
We began our studies of arterial stiffening in HGPS by comparing mechanics and ECM remodeling in the arteries of WT mice versus the progerin-expressing HGPS mouse
The expression of several arterial collagens is elevated in old HGPS mice, our results show that the initiation of arterial stiffening in HGPS is much more closely associated with increased medial Lysyl oxidase (LOX) expression

Summary

Introduction

Hutchinson–Gilford Progeria Syndrome (HGPS) is a rare genetic disease of premature aging. Children with HGPS typically die in their teenage years as a consequence of cardiovascular disease (atherosclerosis, myocardial infarction, heart failure, and/or stroke) (Capell et al, 2007; Gonzalo et al, 2016). Stiff arteries increase load on the heart (Safar, 2010; Laurent & Boutouyrie, 2015), which can have systemic consequences and correlates with cardiac abnormalities such as left ventricular hypertrophy and diastolic dysfunction (Mottram et al, 2005; Kim et al, 2017) Consistent with these relationships, left ventricular hypertrophy and, diastolic dysfunction are observed in HGPS children (Prakash et al, 2018)

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