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

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.

Decreased vascular smooth muscle contractility in Hutchinson–Gilford Progeria Syndrome linked to defective smooth muscle myosin heavy chain expression

“…In this work, we analyzed arterial gene expression and contractility in young (2-month) HPGS mice, before SMC loss is detectable 26 , with the goal of identifying potentially causal events in HPGS pathogenesis. We found a reduced abundance of SM-MHC mRNA and protein that was associated with impaired arterial contraction in isolated HGPS carotid arteries and reduced force generation in isolated HGPS SMCs.…”

Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models

“…Lmna G609G/G609G cardiomyocytes have structural, conduction, and excitation-contraction coupling defects, all of which can be partially corrected by chronic treatment with the microtubule-stabilizing drug paclitaxel [ 49 ]. Vascular alterations include VSMC depletion in the medial layer of the aorta and other arteries, collagen and proteoglycan accumulation in the aortic media, reduced elastin fiber undulations, and increased vessel stiffness assessed by wire and pressure myography [ 45 , 51 , 55 , 56 , 65 ]. Aortic VSMC loss and adventitial fibrosis were also features of a separate Lmna G609G/G609G mouse model developed independently in 2016 by the Fong laboratory [ 54 ].…”

“…Aortic VSMC loss and adventitial fibrosis were also features of a separate Lmna G609G/G609G mouse model developed independently in 2016 by the Fong laboratory [ 54 ]. Compared with age-matched wild-type animals, the aortic and carotid medial layers of Lmna G609G/G609G mice show marked accumulation of the collagen-crosslinking enzyme lysyl oxidase (LOX), which probably contributes to progerin-induced vessel stiffening [ 55 ]. Heterozygous Lmna G609G/+ mice also die prematurely, but their average lifespan (34 weeks) is considerably longer than that of homozygous Lmna G609G/G609G mice (15 weeks) [ 45 ].…”

“…To date, the most widely used experimental system for the study of progerin-induced VSMC alterations in vivo is the Lmna G609G model. Homozygous Lmna G609G/G609G mice show no obvious aortic structural alterations at 8 weeks of age [ 55 , 65 ], but VSMC depletion is evident in the aortic arch at 12–14 weeks [ 45 , 51 ] and also in the thoracic aorta at 17 weeks [ 65 ]. These observations reinforce the idea that HGPS-associated VSMC loss is progressive and that the aortic arch may be especially sensitive to progerin-induced vascular damage, due to environmental factors such as turbulent blood flow and other mechanical cues characteristic of this aortic segment [ 93 ].…”

“…In Lmna G609G/G609G mice, increased vascular stiffness and defective vascular tone were partially prevented by dietary supplementation with sodium nitrite [ 50 , 51 ], and vessel calcification was reduced after pyrophosphate treatment [ 48 ]. Interestingly, LOX inhibition with BAPN prevented carotid stiffening and diastolic dysfunction in 8-week-old Lmna G609G/G609G mice [ 55 ], strongly suggesting that ECM remodeling plays a key role in the acquisition of the HGPS-associated cardiovascular phenotype. Moreover, aortic calcification in heterozygous Lmna G609G/+ mice was reduced by ATP-based therapy or dietary supplementation with magnesium, and this outcome was accompanied by a concomitant increase in lifespan [ 46 , 47 ].…”