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.

Children with Hutchinson–Gilford Progeria Syndrome (HGPS) suffer from multiple cardiovascular pathologies due to the expression of progerin, a mutant form of the nuclear envelope protein Lamin A. Progerin expression has a dramatic effect on arterial smooth muscle cells (SMCs) and results in decreased viability and increased arterial stiffness. However, very little is known about how progerin affects SMC contractility. Here, we studied the LaminAG609G/G609G mouse model of HGPS and found reduced arterial contractility at an early age that correlates with a decrease in smooth muscle myosin heavy chain (SM-MHC) mRNA and protein expression. Traction force microscopy on isolated SMCs from these mice revealed reduced force generation compared to wild-type controls; this effect was phenocopied by depletion of SM-MHC in WT SMCs and overcome by ectopic expression of SM-MHC in HGPS SMCs. Arterial SM-MHC levels are also reduced with age in wild-type mice and humans, suggesting a common defect in arterial contractility in HGPS and normal aging.

Hutchinson-Guilford Progeria Syndrome (HGPS) is a rare genetic disease of premature aging and early death due to cardiovascular disease. The arteries of HGPS children and mice are pathologically stiff, and HGPS mice also display reduced arterial contractility. We recently showed that reduced contractility is an early event in HGPS and linked to an aberrantly low expression of smooth muscle myosin-heavy chain (SM-MHC). Here, we have explored the basis for reduced SM-MHC abundance and asked whether it is a direct effect of progerin expression or a longer-term adaptive response. Myh11, the gene encoding for SM-MHC, is regulated by myocardin-related transcription factors (MRTFs), and we show that HGPS aortas have a reduced MRTF signature. Additionally, smooth muscle cells (SMCs) isolated from HGPS mice display reduced MRTF nuclear localization. Acute progerin expression in WT SMCs phenocopied both the decrease in MRTF nuclear localization and expression of Myh11 seen in HGPS. Interestingly, RNA-mediated depletion of MRTF-A in WT SMCs reproduced the preferential inhibitory effect of progerin on Myh11 mRNA relative to Acta2 mRNA. Our results show that progerin expression acutely disrupts MRTF localization to the nucleus and suggest that the consequent decrease in nuclear coactivator activity can help to explain the reduction in SM-MHC abundance and SMC contractility seen in HGPS.