Abstract: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 contrac… Show more
“…Osorio et al generated a knock-in mouse (Lmna G609G ; hereafter called the HGPS mouse) that contains the equivalent point mutation to the G608G mutation seen in human HGPS ( 42 ). As stated above, the levels of smMHC are reduced in arteries and early passage SMCs isolated from these mice, and this effect is functionally significant: RNAi-mediated knockdown of Myh11 in cultured WT SMCs reproduced the reductions in cell area and traction force seen in HGPS SMCs while overexpression of smMHC restored traction force in HGPS SMCs ( 38 ).…”
Section: Resultsmentioning
confidence: 87%
“…Acute progerin expression even reproduced the stronger reduction in Myh11 mRNA and smMHC protein abundance as compared to Acta2 mRNA and SMA protein ( Fig. 1A , B and C ) that characterizes HGPS SMCs ( 38 ). Figure 1 Acute progerin expression in WT SMCs phenocopies the contractile defects in HGPS SMCs.…”
Section: Resultsmentioning
confidence: 88%
“…Traction force microscopy was performed as previously described ( 38 ). For GFP-progerin experiments, only cells expressing GFP-progerin, as visualized by green fluorescence, were analyzed for traction force microscopy.…”
Section: Methodsmentioning
confidence: 99%
“…We recently reported that aortas, carotid arteries, and cultured SMCs from an HGPS mouse model display reduced expression of SMC contractile markers, including Acta2 and especially Myh11 ( 38 ). Thus, HGPS SMCs have a defective contractile phenotype.…”
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.
“…Osorio et al generated a knock-in mouse (Lmna G609G ; hereafter called the HGPS mouse) that contains the equivalent point mutation to the G608G mutation seen in human HGPS ( 42 ). As stated above, the levels of smMHC are reduced in arteries and early passage SMCs isolated from these mice, and this effect is functionally significant: RNAi-mediated knockdown of Myh11 in cultured WT SMCs reproduced the reductions in cell area and traction force seen in HGPS SMCs while overexpression of smMHC restored traction force in HGPS SMCs ( 38 ).…”
Section: Resultsmentioning
confidence: 87%
“…Acute progerin expression even reproduced the stronger reduction in Myh11 mRNA and smMHC protein abundance as compared to Acta2 mRNA and SMA protein ( Fig. 1A , B and C ) that characterizes HGPS SMCs ( 38 ). Figure 1 Acute progerin expression in WT SMCs phenocopies the contractile defects in HGPS SMCs.…”
Section: Resultsmentioning
confidence: 88%
“…Traction force microscopy was performed as previously described ( 38 ). For GFP-progerin experiments, only cells expressing GFP-progerin, as visualized by green fluorescence, were analyzed for traction force microscopy.…”
Section: Methodsmentioning
confidence: 99%
“…We recently reported that aortas, carotid arteries, and cultured SMCs from an HGPS mouse model display reduced expression of SMC contractile markers, including Acta2 and especially Myh11 ( 38 ). Thus, HGPS SMCs have a defective contractile phenotype.…”
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.
“…These studies showed less expression of contractile markers such as MYH11, calponin, and α-SMA in iSMC derived from HGPS fibroblasts compared to iSMC derived from non-HGPS fibroblasts. These data indicate an effect of progerin hindering the acquisition of a fully differentiated phenotype (Bersini et al, 2020;Pitrez et al, 2020;von Kleeck et al, 2021). In addition, phenotypic changes in VSMC are often associated with vascular calcification due to their capacity to differentiate to osteogenic-like cells.…”
Hutchinson Gilford Progeria Syndrome is a premature aging disease caused by LMNA gene mutation and the production of a truncated lamin A protein, named progerin, that elicits cellular and organismal toxicity. Progerin accumulates in the vasculature, being especially toxic for vascular smooth muscle cells (VSMC). Patients' autopsies show that vessel stiffening, and aortic atherosclerosis is accompanied by VSMC depletion in the medial layer, altered extracellular matrix (ECM), and thickening of the adventitial layer. Mechanisms whereby progerin causes massive VSMC loss and vessel alterations remain poorly understood. Mature VSMC retain phenotypic plasticity and can switch to a synthetic/proliferative phenotype. Here we show that progerin expression in human and mouse VSMC causes a switch towards the synthetic/proliferative phenotype. This switch elicits some level of replication stress in normal cells, which is exacerbated in the presence of progerin, leading to telomere fragility, genomic instability, and ultimately VSMC death. Importantly, calcitriol prevents replication stress, telomere fragility, and genomic instability, reducing VSMC death. In addition, RNAseq analysis shows induction of a profibrotic and proinflammatory aging-associated secretory phenotype upon progerin expression in human primary VSMC. Our data suggest that phenotypic switch-induced replication stress might be an underlying cause of VSMC loss in progeria, which together with loss of contractile features and gain of profibrotic and proinflammatory signatures contribute to vascular stiffness in HGPS. Preventing the phenotypic switch-induced replication stress with compounds such as calcitriol might ameliorate CVD in HGPS patients.
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