Premature arterial stiffening in Hutchinson-Gilford Progeria Syndrome linked to early induction of Lysyl Oxidase (LOX) and corrected by LOX inhibition

Abstract

Arterial stiffening is a hallmark of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the key molecular regulators initiating arterial stiffening in HGPS remain unknown.To identify these early events, we compared arterial mechanics and ECM remodeling in very young HGPS (LMNA G609G/G609G ) mice to those of age-matched and much older wild-type mice.Biaxial inflation-extension tests of carotid arteries of 2-month mice showed that circumferential stiffness of HGPS arteries was comparable to that of 24-month WT controls whereas axial arterial stiffening, an additional hallmark of normal aging, was mostly spared in HGPS. Transmission electron microscopy could identify slightly increased amounts of collagen within the elastin folds of HGPS carotid arteries, but this change was barely detectable by immunostaining carotid cross sections or qPCR of isolated aortas. In contrast, immunostaining and RT-qPCR readily revealed an increased expression of Lysyl oxidase (LOX) and its family members in young HGPS arteries.Moreover, treatment of HGPS mice with the pan-Lox inhibitor -aminopropionitrile (BAPN) restored near-normal circumferential arterial mechanics to HGPS carotid arteries, causally linking LOX upregulation to premature arterial stiffening in HGPS. Finally, we show that this premature increase in arterial LOX expression in HGPS foreshadows the increased expression of LOX that accompanies circumferential arterial stiffening during normal aging.