RT Journal Article SR Electronic T1 Arterial stiffness and cardiac dysfunction in Hutchinson–Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202000997 DO 10.26508/lsa.202000997 VO 4 IS 5 A1 Ryan von Kleeck A1 Emilia Roberts A1 Paola Castagnino A1 Kyle Bruun A1 Sonja A Brankovic A1 Elizabeth A Hawthorne A1 Tina Xu A1 John W Tobias A1 Richard K Assoian YR 2021 UL https://www.life-science-alliance.org/content/4/5/e202000997.abstract 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.