PT  - JOURNAL ARTICLE
AU  - Ryan von Kleeck
AU  - Emilia Roberts
AU  - Paola Castagnino
AU  - Kyle Bruun
AU  - Sonja A Brankovic
AU  - Elizabeth A Hawthorne
AU  - Tina Xu
AU  - John W Tobias
AU  - Richard K Assoian
TI  - Arterial stiffness and cardiac dysfunction in Hutchinson–Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase
AID  - 10.26508/lsa.202000997
DP  - 2021 May 01
TA  - Life Science Alliance
PG  - e202000997
VI  - 4
IP  - 5
4099  - https://www.life-science-alliance.org/content/4/5/e202000997.short
4100  - https://www.life-science-alliance.org/content/4/5/e202000997.full
SO  - Life Sci. Alliance2021 May 01; 4
AB  - 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.