Progerin mislocalizes myocardin-related transcription factor in Hutchinson–Guilford Progeria syndrome

Abstract

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.

Progerin, an Aberrant Spliced Form of Lamin A, Is a Potential Therapeutic Target for HGPS

“…Skin tissue sections from patients with HGPS have shown that progerin accumulates primarily in the nuclei of vascular cells, suggesting that its accumulation has a direct association with vascular diseases in progeria [19]. Similarly, several reports have suggested that progerin in vascular muscles could accelerate atherosclerosis by inducing endoplasmic reticulum (ER) stress, DNA damage, wound healing impairment, mislocalization of a myocardinrelated transcription factor, and replication stress [77][78][79][80][81]. Recently, Hamczyk et al (2018) produced the first mouse model (Apoe -/-Lmna LCS/LCS SM22αCre) with progerin-induced atherosclerosis acceleration expressing progerin specifically in VSMCs and demonstrated that restricting progerin expression to VSMCs is sufficient to accelerate atherosclerosis, trigger plaque vulnerability, and reduce lifespan [66].…”